ES2382163T3 - Heterocyclic compounds substituted with CXCR3 antagonist activity - Google Patents

Abstract

The present application discloses a compound, or enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrug of said compound, or pharmaceutically acceptable salts, solvates or esters of said compound, or of said prodrug, said compound having the general structure shown in Formula 1: or a pharmaceutically acceptable salt, solvate or ester thereof, wherein the various moieties are defined herein. Also disclosed is a method of treating chemokine mediated diseases, such as, palliative therapy, curative therapy, prophylactic therapy of certain diseases and conditions such as inflammatory diseases (non-limiting example(s) include, psoriasis), autoimmune diseases (non-limiting example(s) include, rheumatoid arthritis, multiple sclerosis), graft rejection (non-limiting example(s) include, allograft rejection, xenograft rejection), infectious diseases (e.g, tuberculoid leprosy), fixed drug eruptions, cutaneous delayed-type hypersensitivity responses, type I diabetes, viral meningitis and tumors using a compound of Formula 1.

Description

Heterocyclic compounds substituted with CXCR3 antagonist activity

Field of the Invention

The present invention means heterocyclic compounds substituted with CXCR3 antagonist activity, to pharmaceutical compositions containing one or more such antagonists, one or more such antagonists in combination with other compounds with chemokine activity, one or more such antagonists in combination with known immunosuppressive agents (including as an example, or as examples, non-limiting methotrexate, interferon, cyclosporine, FK-506 and FTY720), to methods for preparing such antagonists and to methods for using such antagonists to modulate CXCR3 activity. The present invention also discloses methods of using such CXCR3 antagonists for the treatment (including, as non-limiting examples, palliative, curative and prophylactic therapies) of diseases and conditions in which CXCR3 is involved. Diseases and conditions in which CXCR3 is involved include, but is not limited to, inflammatory conditions (psoriasis and inflammatory bowel disease), autoimmune diseases (multiple sclerosis, rheumatoid arthritis), drug-fixed rashes, delayed skin hypersensitivity responses, Type I diabetes, viral meningitis and tuberculoid leprosy. The antagonistic activity of CXCR3 has also been indicated as a therapy for tumor suppression as well as for graft rejection (allograft and zenograft rejections, for example).

Background of the invention

Chemokines constitute a family of cytokines that occur during inflammation and regulate leukocyte recruitment (Baggiolini, M. et al., Adv. Immunol., 55: 97-179 (1994); Springer, TA, Annual Rev. Physio ., 57: 827-872 (1995); and Schall, TJ and KB Bacon, Curr. Opin. Immunol, 6: 865-873 (1994)). Chemokines can selectively induce chemotaxis of blood-formed elements (other than red blood cells), including leukocytes such as neutrophils, monocytes, macrophages, eosinophils, basophils, mast cells and lymphocytes, such as T cells and B cells. Stimulate chemotaxis, chemokines can selectively induce other changes in cells that respond to them, including changes in cell form, transient increases in the concentration of intracellular free calcium ions ([Ca2 +] i), granule exocytosis, increased regulation of integrins, formation of bioactive lipids (eg, leukotrienes) and respiratory explosion, associated with the activation of leukocytes. Therefore, chemokines are early triggers of the inflammatory response, causing the release of inflammatory mediators, chemotaxis and extravasation to sites of infection or inflammation.

Chemokines are related in the primary structure and share four conserved cysteines, which form disulfide bonds. Based on this motif of conserved cysteine, the family can be divided into different branches, including CXC chemokines (α-chemokines) in which the first two conserved cysteines are separated by an intermediate moiety (for example, IL-8, IP-10 , Mig, I-TAC, PF4, ENA-78, GCP-2, GROα, GROβ, GROδ, NAP-2, NAP-4), and CC chemokines. (β-chemokines), in which the first two conserved cysteines are adjacent residues (for example, MIP-1α, MIP-1β, RANTES, MCP-1, MCP-2, MCP-3, I-309 (Baggiolini, M and Dahinden, CA, Immunology Today, 15: 127-133 (1994). Most CXC chemokines attract neutrophil leukocytes, for example, CXC chemokines, interleukin-8 (IL-8), GRO alpha (GROα) and neutrophil activating peptide 2 (NAP-2) are potent chemoattractants and neutrophil activators.CXC chemokines called Mig (interferon-induced gamma monovinin) and IP-10 (interferon-gamma-inducible 10 kDa protein) are particularly active in the induction of chemotaxis of activated peripheral blood lymphocytes.

CC chemokines are generally less selective and can attract various cell types of leukocytes including monocytes, eosinophils, basophils, T lymphocytes and natural cytolytic lymphocytes. CC chemokines such as chemotactic proteins of human monocytes 1-3 (MCP-1, MCP-2 and MPC-3), RANTES (Regulated by Activation, Expressed and Secreted by Normal T cells) and inflammatory macrophage proteins 1α and 1β (MIP-1α and MIP-1β) have been characterized as chemoattractants and activators of monocytes or lymphocytes, but do not appear to be chemoattractants for neutrophils.

A chemokine receptor that binds to CXC, IP-10 and Mig chemokines has been cloned, characterized (Loetscher,

M. et al., J. Exp. Med., 184: 963-969 (1996)) and has been called CXCR3. CXCR3 is a G-protein coupled receptor with seven transmembrane domains and has been shown to be expressed restrictively in activated T cells, preferably in human Th1 cells. By binding to the appropriate ligand, chemokine receptors transduce an intracellular signal through the associated G proteins resulting in a rapid increase in intracellular calcium concentration.

The CXCR3 receptor mediates the mobilization and chemotaxis of Ca2 + (calcium ion) in response to IP-10 and Mig. Cells expressing CXCR3 show no significant response to chemokines CXC, IL-8, GROα, NAP-2, GCP-2 (granulocyte chemotactic protein 2), ENA78 (neutrophil activating peptide derived from epithelium 78), PF4 ( platelet factor 4), nor to the chemokines CC, MCP-1, MCP-2, MCP-3, MCP-4, MIP-1α, MIP-1β, RANTES, 1309, eotaxin or lympotactin. In addition, it has also been discovered that a third ligand for CXCR3, I-TAC (Alpha Chemoattractant of

Interferon-inducible T cells) binds to the receptor with high affinity and medium functional responses (Cole, K. E. et al., J. Exp. Med., 187: 2009-2021 (1998)).

Note the restricted expression of human CXCR3 in activated T lymphocytes and the selectivity of the CXCR3 ligand. The human receptor is highly expressed in IL-2 activated T lymphocytes, but was not detected in resting T cells, monocytes or granulocytes (Qin, S. et al., J. Clin. Invest., 101: 746-754 ( 1998)). Additional studies of receptor distribution indicate that most CD3 + cells express CXCR3, including cells that are CD95 +, CD45RO + and CD45RAlow, a phenotype that matches prior activation, although a proportion of CD20 + (B) cells and CD56 + cells ( NK) also express this receptor. Selective expression in activated T lymphocytes is of interest, because other chemokine receptors that have been reported to attract lymphocytes (eg, MCP-1, MCP-2, MCP-3, MIP-1α, MIP-β, RANTES ) are also expressed by granulocytes, such as neutrophils, eosinophils and basophils, as well as monocytes. These results suggest that the CXCR3 receptor is involved in the selective recruitment of effector T cells.

CXCR3 recognizes unusual CXC chemokines, called IP-10, Mig and I-TAC. Although these belong to the CXC subfamily, unlike IL-8 and other CXC chemokines that are potent chemoattractants for neutrophils, the primary targets of IP-10, Mig and I-TAC are lymphocytes, particularly effector cells such as activated or stimulated T lymphocytes and natural cytolytic lymphocytes (NK) (Taub, DD et al., J Exp. Med., 177: 18090-1814 (1993); Taub, DD et al., J. Immunol., 155: 3877-3888 (1995); Cole, KE et al., J. Exp. Med., 187: 2009-2021 (1998)). (NK cells are large granular lymphocytes that lack a specific T-cell receptor for antigen recognition, but possess cytolytic activity against cells such as tumor cells and virus-infected cells.) Consequently, IP-10, Mig and I-TAC lack the ELR motif, an essential binding epitope in CXC chemokines that effectively induce neutrophil chemotaxis (Clark-Lewis, I. et al., J. Biol. Chem. 266: 23128-23134 (1991); Hebert, CA et al., J. Biol. Chem., 266: 18989-18994 (1991); and Clark-Lewis, 1. et al., Proc. Natl. Acad. Sci USA, 90: 3574-3577 (1993)). In addition, it has been reported that both recombinant human Mig and recombinant human IP-10 have been described to induce calcium flow in lymphocyte infiltrating tumors (TIL) (Liao, F. et al., J Exp. Med , 182: 1301-1314 (1995)). While it has been reported that IP-10 induces in vitro monocyte chemotaxis (Taub, DD et al., J. Exp. Med., 177: 1809-1814 (1993), the responsible receptor has not been identified) Human Mig and I-CT seem to be highly selective and show no such effect (Liao, F. et al., J. Exp. Med., 182: 1301-1314 (1995); Cole, KE et al., J. Exp Med., 187: 2009-2021 (1998)). IP-10 expression is induced in various tissues in inflammatory conditions such as psoriasis, drug-fixed rashes, delayed-type skin hypersensitivity responses, and tuberculoid leprosy, as well as tumors and in animal model studies, for example, experimental glomerulonephritis. and experimental allergic encephalomyelitis. IP-10 has a potent antitumor effect in vivo that is dependent on T cells, it has been reported to be an inhibitor of angiogenesis in vivo and can induce chemotaxis and degranulation of NK cells in vitro, suggesting a role as a mediator in the recruitment and degranulation of NK cells (in destruction of tumor cells, for example) (Luster, AD and P. Leder, J. Exp. Med., 178: 1057-1065 (1993); Luster, AD et al., J Exp Med. 182: 219-231 (1995); Angiolillo, AL et al., J. Exp. Med., 182: 155-162 (1995); Taub, DD et al., J. Immunol., 155: 3877 -3888 (1995)). The expression patterns of IP-10, Mig and I-TAC are also different from the other CXC chemokines since the expression of each is induced by interferon-gamma (IFN-δ), while the expression of IL-8 is regulates IFN-δ by decrease (Luster, AD et al., Nature, 315: 672-676 (1985); Farber, JM, Proc. Natl. Acad. Sci. USA, 87: 5238-5242 (1990); Farber, JM, Biochem. Biophys. Res. Commun., 1921): 223-230 (1993), Liao, F. et al., J. Exp. Med., 182: 1301-1314 (1995); Seitz, M. et al., J. Clin. Invest., 87: 463-469 (1991); Galy, A. H. M. and H. Spits, J. Immunol., 147: 3823-3830 (1991); Cole, K. E. et al., J. Exp. Med., 187: 2009-2021 (1998)).

Chemokines are recognized as mediators for so long sought for lymphocyte recruitment. Several CC chemokines have been found to cause lymphocyte chemotaxis (Loetscher, P. et al., FASEB J., 8: 1055-1060 (1994)), however, they are also active on granulocytes and monocytes (Uguccioni, M et al., Eur. J. Immunol., 25: 64-68 (1995); Baggiolini, M. and CA Dahinden, Immunol. Today, 15: 127-133 (1994)). The situation is different for IP-10, Mig and I-TAC, which are selective in their action on lymphocytes, including activated T lymphocytes and NK cells and that bind to CXCR3, a receptor that does not recognize numerous other chemokines and that has a selective expression pattern.

In view of these observations, it is reasonable to conclude that the formation of characteristic infiltrates in inflammatory lesions such as, for example, delayed-type hypersensitivity lesions, viral infection sites and certain tumors is a CXCR3-mediated process regulated by CXCR3 expression. Lymphocytes, particularly T lymphocytes, which carry a CXCR3 receptor as a result of activation, can be recruited into inflammatory lesions, sites of infection and / or tumors by IP-10, Mig and / or I-TAC, which can be induced locally by interferon gamma. In this way, CXCR3 plays a role in the selective recruitment of lymphocytes, particularly effector cells such as activated or stimulated T lymphocytes. Consequently, activated and effector T cells have been implicated in numerous pathologies such as graft rejection, inflammation, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and psoriasis. In this way, CXCR3 represents a promising target for the development of new therapeutic agents.

Reference is made to EP1048652A1 (published on November 2, 2000), which means aromatic compounds that possess cyclic amino or salts thereof, that specifically inhibit FXa, which exert a potent anticoagulant effect and are therefore useful as medicinal compositions.

Reference is made to PCT Publication No. WO 93/10091 (Applicant: Glaxo Group Limited, Published May 27, 1993) which discloses derivatives of piperidine acetic acid as inhibitors of fibrinogen-dependent blood platelet aggregation possessing the formula:

An illustrative compound of this series is:

Reference is also made to PCT Publication No. WO 99/20606 (Applicant: J. Uriach & CIA. S.A., published on April 29, 1999) which discloses piperazines as inhibitors of platelet aggregation that have the formula:

10 Reference is also made to United States Patent Application No. US2002 / 0018776 A1 (Applicant: Hancock, et al., Published February 14, 2002) which discloses graft rejection treatment procedures.

Reference is also made to PCT Publication No. WO 03/098185 A2 (Applicant: Renew, Inc., published November 27, 2003) which discloses diagnostic procedures and prediction of organ transplant rejection by chemokine detection, for example , chemokines CXCR3 and CCL in urine.

15 Reference is also made to PCT Publication No. WO 03/082335 A1 (Applicant: Sumitomo Pharmaceuticals Co. Ltd., published October 9, 2003), which discloses procedures for scanning a CXCR3 ligand and diagnostic procedures for Type 2 diabetes by detecting the expression dose of a CXCR3 ligand in a biological sample.

Reference is also made to PCT Publication No. WO 02/085861 (Applicant: Millennium Pharmaceuticals, Inc.

20 published on October 31, 2002) which discloses imidizalolidine compounds and their use as CXCR3 antagonists that have the formula:

An illustrative compound of this series is:

Reference is also made to PCT Publication No. WO 03/101970 (Applicant: Smithkline Beecham Corporation, published on December 11, 2003) which discloses imidazolium compounds and their use as CXCR3 antagonists that possess the formula:

An illustrative example of this series is:

Reference is also made to US Patent Application No. US 2003/0055054 A1 (Applicant: Medina et al, published on March 20, 2003) and related Patent US 6 794 379 B2 (Applicant: Medina et al, published on September 21, 2004) which discloses compounds with CXCR3 activity that have the formula:

An illustrative compound of this series is:

Reference is also made to US Patent No. 6,124,319 (Applicant: MacCoss et al., Filed September 6, 2000) which discloses compounds useful as chemokine receptor modulators that possess the formula:

Reference is also made to PCT Publication WO 03/070242 A1 (Applicant: CELLTECH R & D limited, published on August 28, 2003) which discloses useful compounds such as "chemokine receptor inhibitors for the treatment of inflammatory diseases" possessing the formula :

Reference is also made to PCT Publication WO 04/074287 A1, WO 04/074273 A1, WO 04/74278 (Applicant: AstraZeneca R&D published February 19, 2004) which discloses pyridine derivatives, processes for their preparation and its use in the modulation of autoimmune diseases that have the formula:

10 in which R3 is phenyl, or an aromatic ring of 5 or 6 members with 1 or more nitrogen atoms.

Reference is also made to US 6,391,865 B1 which discloses piperazine derivatives useful as CCR5 antagonists.

There is a need for compounds that are capable of modulating the activity of CXCR3. For example, there is a need for new treatments and therapies for diseases and conditions associated with CXCR3 such as

15 inflammatory conditions (psoriasis and inflammatory bowel disease), autoimmune diseases (multiple sclerosis, rheumatoid arthritis) and graft rejection (allograft and zenograft rejection, for example) as well as infectious diseases, cancers and tumors, drug-fixed rashes, drug responses delayed skin hypersensitivity, type I diabetes, viral meningitis and tuberculoid leprosy.

There is a need for treatment or prevention or improvement procedures for one or more disease symptoms and

20 conditions associated with CXCR3. There is a need for procedures to modulate the activity of CXCR3 using the compounds provided herein.

Summary of the Invention

In its many embodiments, the present invention discloses a compound having the general structure shown in Formula 1:

or a pharmaceutically acceptable salt, solvate or ester thereof, in which:

G is selected from the group consisting of H, hydroxyl, alkoxy, R2R1N-, R2R1X-C (R14) (R1S) - and a 5-membered heteroaryl or heterocyclynyl ring containing at least one -C = N- moiety as part of said heteroaryl or heterocyclynyl ring and which is selected from the group consisting of dihydroimidazole, imidazole, dihydrooxazol, oxazol, dihydrooxadiazole, oxadiazole, triazole and tetrazole, wherein said heteroaryl or heterocyclynyl ring may be both (i) unsubstituted, and (ii) optionally independently substituted in one or more carbon atoms in the ring with one or more R9 substituents, or in one or more ring nitrogen atoms with one or more R8 substituents, wherein said R8 and R9 substituents may be same or different; L is O Z is No CR4; R1 and R2 are absent or present independently, and if present, each is independently selected from the group consisting of H, alkyl, alkoxy, alkenyl, carbonyl, cycloalkyl, cycloalkenyl, alkylaryl, arylalkyl, aryl, amino, alkylamino, amidinyl , carboxamido, cyano, hydroxyl, urea, -N≡CH, = NCN, - (CH2) qOH, - (CH2) qOR31, - (CH2) qNH2, - (CH2) qNHR31, (CH2) qN (R31) 2, - (CH2) qC (= O) NHR31, - (CH2) qSO2R31, - (CH2) qNHSO2R31, - (CH2) qSO2NHR31, C (= S) N (H) alkyl, -N (H) -S (O) 2-alkyl, -N (H) C (= O) N (H) -alkyl, -S (O) 2alkyl, -S (O) 2N (H) alkyl, - S (O) 2N (alkyl) 2, -S (O) 2-aryl, -C (= S) N (H) cycloalkyl, -C (= O) N (H) NH2, -C (= O) alkyl, -heteroaryl, heterocyclyl and heterocyclyl; or alternatively, when X is N, the N taken together with R1 and R2 forms a heterocyclyl, heteroaryl or -N = C (NH2) 2; R3 is selected from -H, -Cl and -CH3 the R4 moieties may be the same or different, each independently being selected from the group consisting of H, alkyl, alkylaryl, aralkyl, -CN, CF3, haloalkyl, cycloalkyl, halogen, hydroxyalkyl, -N = CH- (R31), -C (= O) N (R30) 2, -N (R30) 2, -OR30, -SO2 (R31), -N (R30) C (= O) N (R30) 2 and -N (R30) C (= O) R31; R6 is selected from the group consisting of H and alkyl, X is selected from the group consisting of N, O, alkyl, cycloalkyl, heteroaryl, heterocyclyl and heterocyclyl; R8 moieties may be the same or different, each independently being selected from the group consisting of H, alkyl, alkenyl, alkylaryl, arylalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, - (CH2) qOH, - (CH2) qOR31, - (CH2) qNH2, - (CH2) qNHR31, - (CH2) qC (= O) NHR31, - (CH2) qSO2R31, - (CH2) qNSO2R31 and - (CH2) qSO) 2NHR31; residues R9 may be the same or different, each independently being selected from the group consisting of -NH2 and -N (H) CH2CH3 residues R10 may be the same or different, each independently selected from the group consisting of CH3, CH2CH3 and -CH2 CH2 CH3 the R11 moieties may be the same or different, each independently selected from the group consisting of H and CH3 the R12 moieties are -H the D rings are selected from phenyl and pyridinyl, in which the D ring is unsubstituted or optionally substituted with 1-5 independently selected R20 moieties; R20 moieties may be the same or different, each independently selected from the group consisting of H, halogen and amino. R21 moieties may be the same or different, each independently being selected from the group consisting of H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, alkylthiocarboxy, alkylheteroaryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, aminoalkyl, amidinyl, aralkyl , aralkenyl, aralkoxy, aralkoxycarbonyl, aralkylthio, aryl, aroyl, aryloxy, carboxamido, cyano, cycloalkyl, cycloalkenyl, formyl, guanidinyl, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, heterocyclenyl, hydroxyalkyl, hydroxamate, nitro, trifluoromethoxy, - (CH2 ) qOH, - (CH2) qOR31, - (CH2) q-NH2, - (CH2) qNHR31, - (CH2) qC (= O) NHR31, - (CH2) qSO2R31, - (CH2) qNSO2R31, - (CH2) qSO2NHR31, -alquinylC (R31) 2-OR31, -C (= O) R30, -C (= O) N (R30) 2,

-C (= NR30) NHR30, -C (= NOH) N (R30) 2, -C (= NOR31) N (R30) 2, -C (= O) OR31, -N (R30) 2; -N (R30) C (= O) R31, -NHC (= O) N (R30) 2, -N (R30) C (= O) OR31, -N (R30) C (= NCN) N (R30) 2, -N (R30) C (= O) N (R30) SO2 (R31), -N (R30) C (= O) N (R30) 2, -N (R30) SO2 (R31), -N (R30) S (O) 2N (R30) 2, -OR30, -OC (= O) N (R30) 2, -SR30, -SO2N (R30) 2, -SO2 (R31), -OSO2 (R31) and -OSi (R30) 3; And it is selected from the group consisting of -CH2 - and -C (= O) - R13 residues may be the same or different, each independently selected from the group that It consists of H, alkyl, alkylaryl, cycloalkyl, alkoxy, aryl, heteroaryl, heterocyclynyl, heterocyclyl, spiroalkyl, -CN, -CO2H, -C (= O) R30, -C (= O) N (R30) 2, - (CHR30) qOH, - (CHR30) qOR31, - (CHR30) qNH2, - (CHR30) qNHR31, - (CH2) qC (= O) NHR31, - (CH2) q-SO2R31, - (CH2) qNSO2R31, - (CH2) qSO2NHR31, -NH2, -N (R30) 2, -N (R30) C (= O ) N (R30) 2, -N (R30) SO2 (R31), -OH, OR30, -SO2N (R30) 2 and -SO2 (R31); R14 and R15 are the same or different, each independently selected from the group consisting of H, alkyl, alkylaryl, heteroaryl, hydroxy, -CN, alkoxy, alkylamino, -N (H) S (O) 2alkyl and -N (H) C (= O) N (H) alkyl; or alternatively R14 and R15 taken together are = O, = S, = NH, = N (alkyl), = N (Oalkyl), = N (OH) or cycloalkyl; R30 residues may be the same or different, each independently selected from the group that consists of H, alkyl, alkylaryl, aryl, aralkyl, cycloalkyl, - (CH2) qOH, - (CH2) qOalkyl, - (CH2) qOalkylaryl, - (CH2) qOaryl, - (CH2) qOaralkyl, - (CH2) qOcycloalkyl, - (CH2) qNH2, - (CH2) qNHalkyl, - (CH2) qN (alkyl) 2, - (CH2) qNHalkylaryl, - (CH2) qNHaryl, - (CH2) qN-Haralkyl, - (CH2) qNHcycloalkyl, - (CH2) qC (= O) NHalkyl, - (CH2) qC (= O) N (alkyl) 2, - (CH2) qC (= O) NHalkylaryl, - (CH2) qC (= O) NHaryl, - (CH2) qC (= O) NHaralkyl, - (CH2) qC (= O) NHcycloalkyl, - (CH2) qSO2alkyl, - (CH2) qSO2alkylaryl, - (CH2) q-SO2aryl, - (CH2) qSO2aralkyl, - (CH2) qSO2cycloalkyl, - (CH2) qNSO2alkyl, - (CH2) qNSO2alkylaryl, - (CH2) qNSO2aryl, - (CH2) qNSO2aralkyl, - (CH2) qNSO2cycloalkyl, - (CH2) qSO2NHalkyl, - (CH2) qSO2NHalkylaryl, - (CH2) qSO2NHaryl, - (CH2) qSO2NHaralkyl, - (CH2) qSO2NHcycloalkyl, heterocyclyl, heterocyclyl and heteroaryl; R31 residues may be the same or different, each independently selected from the group that consists of alkyl, alkylaryl, aryl, aralkyl, cycloalkyl, - (CH2) qOH, - (CH2) qOalkyl, - (CH2) qOalkylaryl, - (CH2) qOaryl, - (CH2) qOaralkyl, - (CH2) qOcycloalkyl, - (CH2) qNH2, - (CH2) qNHalkyl, - (CH2) qN (alkyl) 2, - (CH2) qNHalkylaryl, - (CH2) qNHaryl, - (CH2) qN-Haralkyl, - (CH2) qNHcycloalkyl, - (CH2) qC (= O) NHalkyl, - (CH2) qC (= O) N (alkyl) 2, - (CH2) qC (= O) NHalkylaryl, - (CH2) qC (= O) NHaryl, - (CH2) qC (= O) NHaralkyl, - (CH2) qC (= O) NHcycloalkyl, - (CH2) qSO2alkyl, - (CH2) qSO2alkylaryl, - (CH2) q-SO2aryl, - (CH2) qSO2aralkyl, - (CH2) qSO2cycloalkyl, - (CH2) qNSO2alkyl, - (CH2) qNSO2alkylaryl, - (CH2) qNSO2aryl, - (CH2) qNSO2aralkyl, - (CH2) qNSO2cycloalkyl, - (CH2) qSO2NHalkyl, - (CH2) qSO2NHalkylaryl, - (CH2) qSO2NHaryl, - (CH2) qSO2NHaralkyl, - (CH2) qSO2NHcycloalkyl, heterocyclyl, heterocyclyl and heteroaryl; m is 0 to 2; n is from 0 to 4; Y each q may be the same or different, each time being independently selected from 1 to 5; in which the following definitions apply: "heteroaryl" means an aromatic, monocyclic or multicyclic ring system, comprising about 5 to about 14 atoms in the ring, in which one or more of the atoms in the ring are a different element of carbon; the "heteroaryl" may be optionally substituted; "heterocyclynyl" means a partially unsaturated monocyclic or partially multicyclic ring system unsaturated comprising from about 5 to about 14 atoms in the ring, in which one or more of the atoms in the ring are a different element of carbon; the "heterocyclenyl" may optionally be replaced; "heterocyclyl" (or heterocycloalkyl) means a saturated non-aromatic monocyclic ring system or multicyclic comprising from about 3 to about 10 atoms in the ring, in which one or more of the Atoms in the ring system are a distinct element of carbon; the heterocyclyl can be optionally replaced; with the proviso that there are not two adjacent double bonds in any ring, and that when a nitrogen is substituted with two alkyl groups, said two alkyl groups can optionally be linked together to form a ring.

A further feature of the invention is a pharmaceutical composition containing as an active ingredient, at least one compound of Formula 1, together with at least one pharmaceutically acceptable excipient or vehicle.

The invention provides processes for preparing compounds of Formula 1, as well as processes

for the treatment of diseases, for example, treatment (for example, palliative therapy, curative therapy, prophylactic therapy) of certain diseases and conditions, for example, inflammatory diseases (for example, psoriasis), autoimmune diseases (for example, rheumatoid arthritis, multiple sclerosis), graft rejection (for example, allograft rejection, xenograft rejection), infectious diseases and tumors. The invention provides a method for treating a CXCR3 chemokine-mediated disease, in a patient in need of such treatment, which comprises administering to the patient a therapeutically effective amount of at least one compound of Formula 1, or a pharmaceutically acceptable salt, solvate or ester. acceptable.

The invention provides methods for treating diseases, for example, treatment (for example, palliative therapy, curative therapy, prophylactic therapy) of certain diseases or disorders, such as inflammatory diseases (eg, psoriasis), autoimmune diseases (eg, rheumatoid arthritis , multiple sclerosis), graft rejection (for example, allograft rejection, xenograft rejection), infectious diseases, as well as cancers and tumors, drug-fixed rashes, delayed cutaneous hypersensitivity responses, type I diabetes, viral meningitis and tuberculoid leprosy comprising administering: (a) a therapeutically effective amount of at least one compound according to Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof at the same time or sequentially with (b) at least a medicine selected from the group consisting of: modifying anti-rheumatic drugs the illness; non-steroidal anti-inflammatory drugs; selective COX-2 inhibitors; COX-1 inhibitors; immunosuppressants; steroids; PDE IV inhibitors, anti-TNF-α compounds, MMP inhibitors, glucocorticoids, other chemokine inhibitors, such as CCR2 and CCR5, selective CB2 inhibitors and other classes of compounds indicated for the treatment of rheumatoid arthritis.

The invention also provides a method of modulation (inhibition or promotion) of an inflammatory response in an individual in need of such therapy. The method comprises administering a therapeutically effective amount of a compound (eg, small organic molecule) that inhibits or promotes CXCR3 function in animals, in an individual in need. A method for inhibiting or blocking T lymphocyte-mediated chemotaxis is also disclosed in a patient in need of such treatment, which comprises administering to the patient a therapeutically effective amount of a compound of Formula 1 or a pharmaceutically acceptable salt, solvate or ester thereof. acceptable.

A procedure for treating inflammatory bowel disease is also disclosed in a patient in need of such treatment, which comprises administering to the patient a therapeutically effective amount of at least one compound of Formula 1, or a salt, a solvate or an ester of the same pharmaceutically acceptable.

A procedure for treating implant rejection is also disclosed in a patient in need of such treatment, which comprises administering to the patient a therapeutically effective amount of at least one compound of Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof. .

A method for treating multiple sclerosis is also disclosed in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of: (a) a therapeutically effective amount of at least one compound of Formula 1, or a salt, a pharmaceutically acceptable solvate or ester thereof at the same time or sequentially with (b) at least one compound selected from the group consisting of: glatiramer acetate, glucocorticoids, methotrexate, azothioprine, mitoxantrone and selective CB2 inhibitors.

A method for treating rheumatoid arthritis is also disclosed in a patient in need of such treatment, the procedure comprising administering to the patient a therapeutically effective amount of: (a) at least one compound of Formula 1, or a salt, a solvate or a pharmaceutically acceptable ester thereof, simultaneously or sequentially with (b) at least one compound selected from the group consisting of: COX-2 inhibitors, COX-1 inhibitors, immunosuppressants, steroids, PDE IV inhibitors, anti compounds -TNF-α, MMP inhibitors, glucocorticoids, chemokine inhibitors, selective CB2 inhibitors, cas-pass inhibitors (ICE) and other classes of compounds indicated for the treatment of rheumatoid arthritis.

A method for treating psoriasis is also disclosed in a patient in need of such treatment, the procedure comprising administering to the patient a therapeutically effective amount of: a) at least one compound of Formula 1, or a salt, a solvate or an ester of the same pharmaceutically acceptable, simultaneously or sequentially with (b) at least one compound selected from the group consisting of: immunosuppressants, steroids and anti-TNF-α compounds.

The invention also provides a method for treating a disease selected from the group consisting of: inflammatory disease, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, implant rejection and psoriasis, in a patient in need of such treatment, said method comprising administering to the patient an effective amount of at least one compound of Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof.

The invention also provides a method for treating a disease selected from the group consisting of: inflammatory disease, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, implant rejection, psoriasis, drug-fixed rashes, delayed-type skin hypersensitivity responses , type I diabetes, viral meningitis, tuberculoid leprosy, as well as tumors and cancers in a patient in need of said treatment, said method comprising administering to the patient an effective amount of (a) at least one compound according to Claim 1, or a pharmaceutically acceptable salt farm, solvate or ester thereof, at the same time or sequentially with (b) at least one drug selected from the group consisting of: disease modifying anti-rheumatic drugs; non-steroidal anti-inflammatory drugs; selective COX-2 inhibitors; COX-1 inhibitors; immunosuppressants; steroids; PDE IV inhibitors, anti-TNF-α compounds, MMP inhibitors, glucocorticoids, chemokine inhibitors, selective CB2 inhibitors, biological response modifiers; anti-inflammatory and therapeutic agents.

Detailed description of the invention

The terms used in this document have their usual meaning and the meaning of these terms is independent in each occurrence thereof. However, and unless otherwise indicated, the following definitions apply throughout the specification and claims. Chemical name, common name and chemical structures can be used interchangeably to describe the same structure. These definitions apply regardless of whether a term is used on its own or in conjunction with other terms, unless otherwise indicated. Therefore, the definition of "alkyl" applies to "alkyl", as well as to the "alkyl" portions of "hydroxyalkyl", "haloalkyl", "alkoxy", etc.

As previously used, and throughout the specification, the following terms, unless otherwise indicated, should be construed to have the following meanings:

"Acyl" means a group HC (= O) -, alkyl-C (= O) -, alkenyl-C (= O) -, alkynyl-C (= O) -, cycloalkyl-C (= O) -, cycloalkenyl -C (= O) - or cycloalkynyl-C (= O) -, in which the various groups are as previously described. The bond with the parental residue is made through the carbonyl carbon atom. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl and cyclohexanoyl.

"Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond, which can be linear or branched and comprising from about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have from about 2 to about 12 carbon atoms in the chain; and more preferably from about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. "Lower alkenyl" means from about 2 to about 6 carbon atoms in the chain that can be linear or branched. The alkenyl group may be substituted with one or more substituents that may be the same or different, each substituent being independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, aryl, aryloxy, cycloalkyl, cycloalkenyl, cyano, heteroaryl, heterocyclyl, amino, aminosulfonyl, halo, carboxyl, carboxyalkyl (the example or non-limiting examples include ester), alkoxycarbonyl, hydroxyalkyl, carbonyl (the example or non-limiting examples include ketone), -C (= O) heterocyclyl, formyl (the example or examples Non-limiting include aldehyde), carboxamido (ie, amido, -C (= O) NH2), -C (= O) N (alkyl) 2, -C (= O) NH (alkyl), -C (= O ) N (cycloalkyl) 2, -C (= O) NH (cycloalkyl), -NHC (= O) alkyl, urea (for example, -NH (C = O) NH2, -NH (C = O) NH (alkyl ), -NH (C = O) NH (alkyl) 2, -NH (C = O) NH (heteroaryl); -NH (C = O) NH (heterocyclyl)), guanidinyl, -NHC (= NCN) NH2, -NHC (= NCN) N (alkyl) 2, carbamoyl (i.e. -CO2NH2), NHC (= O) Oalkyl, -CO2N (alkyl) 2, -NHC (= O)) NH-S (O) 2alkyl, -NHC (= O) N (alkyl) 2-S (O) 2alkyl, -NH-S (O) 2alkyl, -NH-S (O) 2heteroaryl , -N (alkyl) -S (O) 2alkyl, -NH-S (O) 2aryl, -N (alkyl) -S (O) 2aryl, -NH-S (O) 2NH2, -NH-S (O) 2NHalkyl, -NH-S (O) 2N (alkyl) 2, alkylthiocarboxy, -S (O) 2alkyl, -S (O) 2aryl, -OS (O) 2alkyl, -OS (O) 2aryl, sulfonyl urea (example or non-limiting examples include NHC (= S) NHalkyl). Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

"Alkyl" means an aliphatic hydrocarbon group that can be linear, branched or a combination thereof, and comprising from about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain from about 1 to about 12 carbon atoms in the chain. The most preferred alkyl groups contain from about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having from about 1 to about 6 carbon atoms in the chain that can be linear or branched. The alkyl group may be substituted with one or more substituents that may be the same or different, each substituent being independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, aryl, aryloxy, cycloalkyl, cycloalkenyl, cyano, heteroaryl, heterocyclyl, amino, -NH (alkyl), -N (alkyl) 2, -NH (cycloalkyl), -N (cycloalkyl) 2, -NH (aryl), -N (aryl) 2, -NH (heteroaryl), -N ( heteroaryl) 2, -NH (heterocyclyl), N (heterocyclyl) 2, halo, hydroxy, carboxyl, carboxyalkyl (the example or non-limiting examples include ester), alkoxycarbonyl, hydroxyalkyl, carbonyl (the example or non-limiting examples include ketone), -C (= O) heterocyclyl, formyl, carboxamido (ie, amido, -C (= O) NH2, -C (= O) N (alkyl) 2, -C (= O) NH (alkyl), -C (= O) N (cycloalkyl) 2, -C (= O) NH (cycloalkyl)), -NHC (= O) alkyl, amidinyl, hydrazidyl, hydroxamate, -NHC (= O) H, -NHC (= O) alkyl, urea (for example, -NH (C = O) NH2, -NH (C = O) NH (alkyl), -NH (C = O) NH (alkyl) 2,

-

NH (C = O) NH (heteroaryl), -NH (C = O) NH (heterocyclyl)), guanidinyl, -NHC (= NCN) NH2, -NHC (= NCN) N (alkyl) 2, carbamoyl (i.e. , -CO2NH2), -NHC (= O) Oalkyl, -CO2N (alkyl) 2, = NHC (= O) NH-S (O) 2alkyl, -NHC (= O) N (alkyl) -S (O) 2alkyl ; -NH-S (O) 2alkyl, -NH-S (O) 2heteroaryl, -N (alkyl) -S (O) 2alkyl, -NH-S (O) 2aryl, -N (alkyl) -S (O) 2aryl , -NH-S (O) 2NH2, -NH-S (O) 2NHalkyl, -NH-S (O) 2N (alkyl) 2, thio, alkylthio, alkylthiocarboxy, -S (O) alkyl, -S (O) 2alkyl, -S (O) 2aryl, -OS (O) 2alkyl, -OS (O) 2aryl, sulfonyl urea (the example or non-limiting examples include -NHC (= S) NHalkyl) and OSi (alkyl) 3. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl, decyl, fluoromethyl, trifluoromethyl and cyclopropylmethyl.

"Alkylheteroaryl" means an alkyl-heteroaryl- group in which the alkyl is as described above and the binding to the precursor molecular moiety is through the heteroaryl group.

"Alkylamino" means a group -NH2 or -NH3 + in which one or more of the hydrogen atoms in the nitrogen is replaced by an alkyl group as defined above. The bond to the precursor compound is through nitrogen.

"Alkylaryl" means an alkyl-aryl- group in which the alkyl and aryl are as described herein. Preferred alkylaryls comprise a lower alkyl group. Non-limiting examples of suitable alkylaryl groups include o-tolyl, p-tolyl and xylyl. The link with the parental remainder is made through the aryl.

"Alkylthio" means an alkyl-S- group, in which the alkyl group is as described herein. Non-limiting examples of suitable alkylthio groups include methylthio, ethylthio, i-propylthio and heptyl. The bond with the parental remainder is made through sulfur.

"Alkylthiocarboxy" means an alkyl-S-C (= O) O- group. Preferred groups are those in which the alkyl group is lower alkyl. The link with the parental remainder is done through the carboxy.

"Alkylsulfonyl" means an alkyl-S (O) 2- group. Preferred groups are those in which the alkyl group is lower alkyl. The bonding with the parental residue is done through the sulfonyl.

"Alkylsulfinyl" means an alkyl-S (O) - group. Preferred groups are those in which the alkyl group is lower alkyl. The bond with the parental residue is done through sulfinyl.

"Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, which can be linear or branched and comprising from about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have from about 2 to about 12 carbon atoms in the chain; and more preferably from about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to the linear alkynyl chain. "Lower alkynyl" means from about 2 to about 6 carbon atoms in the chain that can be linear or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl, 3-methylbutinyl, n-pentinyl and decinyl. The alkynyl group may be substituted with one or more substituents that may be the same or different, each substituent being independently selected from the group consisting of alkyl, alkoxy, aryl, aryloxy, cycloalkyl, cycloalkenyl, cyano, heteroaryl, heterocyclyl, -NH (alkyl ), -N (alkyl) 2, -NH (cycloalkyl), -N (cycloalkyl) 2, -NH (aryl), -N (aryl) 2, -NH (heteroaryl), -N (heteroaryl) 2, -NH (heterocyclyl), N (heterocyclyl) 2, alkoxycarbonyl, hydroxyalkyl, carbonyl (the example or non-limiting examples include ketone), -C (= O) heterocyclyl, carboxamido (i.e., amido, -C (= O) NH2), -C (= O) N (alkyl) 2, -C (= O) NH (alkyl), -C (= O) N (cycloalkyl) 2, -C (= O) NH (cycloalkyl), alkylC (= O ) NH-, -NHC (= O) alkyl, urea (for example, -NH (C = O) NH2), -NH (C = O) NH (alkyl), -NH (C = O) NH (alkyl) 2, -NH (C = O) NH (heteroaryl), -NH (C = O) NH (heterocyclyl), -S (O) 2alkyl and -S (O) 2aryl.

"Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, heptoxy and methylhydroxy. The bonding with the parental residue is done through the oxygen of the ether.

"Alkoxycarbonyl" means an alkyl-O-C (= O) - group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond with the parental residue is done through carbonyl.

"Aminoalkyl" means an amine-alkyl- group, in which alkyl is as defined above. Preferred aminoalkyls contain lower alkyl. Non-limiting examples of suitable aminoalkyl groups include aminomethyl and 2-Dimethylamino-2-ethyl. The bond with the parental residue is done through the alkyl.

"Amidinyl" means a group -C (= NR) NHR. The R groups are defined as H, alkyl, alkylaryl, heteroaryl, hydroxy, alkoxy, amino, ester, -NHSO2alkyl, -NHSO2aryl, -NHC (= O) NHalkyl and -NHalkyl. The bond with the parental rest is done through carbon.

"Aralkyl" or "arylalkyl" means an aryl-alkyl- group, in which aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group attached to the aryl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The link with the parental rest

It is done through the alkyl.

"Aralkenyl" means an aryl-alkenyl- group, in which aryl and alkenyl are as previously described. Preferred aralkenyls contain a lower alkenyl group. Non-limiting examples of suitable aralkenyl groups include 2-phenetenyl and 2-naphthyletenyl. The connection with the parental residue is done through the alkenyl.

"Aralkylthio" means an aralkyl-S- group, in which the aralkyl group is as described above. A non-limiting example of a suitable aralkylthio group is benzylthio. The bond with the parental remainder is made through sulfur.

"Aralkoxy" means an aralkyl-O- group, in which the aralkyl group is as described above. The bond with the parental residue is done through the oxygen group.

"Aralkoxycarbonyl" means an aralkyl-O-C (= O) - group. A non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond with the parental residue is done through carbonyl.

"Aroyl" means an aryl-C group (= O) -, in which the aryl group is as described above. The bond with the parental residue is done through carbonyl. Non-limiting examples of suitable groups include benzoyl and 1- and 2-naphthoyl.

"Aryl" (sometimes abbreviated "Ar") means an aromatic, monocyclic or multicyclic ring system, comprising from about 6 to about 14 carbon atoms, preferably from about 6 to about 10 carbon atoms. The aryl group may be optionally substituted with one or more "ring system substituents" that may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.

"Aryloxy" means an aryl-O- group, in which the aryl group is as described above. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bonding with the parental residue is done through the oxygen of the ether.

"Arylsulfonyl" means an aryl-S (O) 2- group. The bonding with the parental residue is done through the sulfonyl.

"Arylsulfinyl" means an aryl-S (O) - group. The bond with the parental residue is done through sulfinyl.

"Arylthio" means an aryl-S- group, in which the aryl group is as described above. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bond with the parental remainder is made through sulfur.

"Carboxyalkyl" means an alkyl-C (= O) O- group. The link with the parental remainder is done through the carboxy.

Carbamates and urea substituents mean groups with oxygen and nitrogen respectively, adjacent to an amide; Representative carbamate and urea substituents include the following:

"Cycloalkyl" means a mono- or multicyclic, non-aromatic ring system comprising from about 3 to about 10 carbon atoms, preferably from about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain from about 5 to about 7 ring atoms. The cycloalkyl may be optionally substituted with one or more "ring system substituents" which

they can be the same or different, and they are as defined above. Non-limiting examples of suitable monocyclic cycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyl include 1-decalino, norbornyl, adamantyl and the like.

"Cycloalkenyl" means a mono or multicyclic, non-aromatic ring system comprising from about 3 to about 10 carbon atoms, preferably from about 5 to about 10 carbon atoms containing at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain from about 5 to about 7 ring atoms. The cycloalkenyl may be optionally substituted with one or more "ring system substituents" that may be the same or different, and are as defined above. Non-limiting examples of monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cycloheptenyl and the like. A non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.

"Halogen" (or halo) means fluorine, chlorine, bromine or iodine. Fluorine, chlorine and bromine are preferred.

"Haloalkyl" means an alkyl as defined above, in which one or more atoms of the hydrogens in the alkyl is replaced by a halo group defined above. Non-limiting examples include trifluoromethyl, 2,2,2-trifluoroethyl, 2-chloropropyl and the like.

"Heteroaryl" means an aromatic, monocyclic or multicyclic ring system, comprising from about 5 to about 14 atoms in the ring, preferably from about 5 to about 10 atoms in the ring, in which one or more of the atoms in the ring Ring are a different element of carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain from about 5 to about 6 ring atoms. The "heteroaryl" may be optionally substituted with one or more "ring system substituents" that may be the same or different, and are as defined herein. The prefix aza, oxa or aunt before the root name of the heteroaryl means that at least one nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. The nitrogen or sulfur atom of the heteroaryl can optionally be oxidized to give the corresponding N-oxide, S-oxide or S, S-dioxide. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalzyl, iminoxlazyl [1,2-a] pyridinyl, imidazo [2,1-b] thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzoimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyrolylyl, imidazopyridyl, benzoimidazolenedinyl , 4-triazinyl, benzothiazolyl and the like.

"Heterocyclenyl" means a partially unsaturated monocyclic or partially unsaturated multicyclic ring system, comprising from about 5 to about 14 atoms in the ring, preferably from about 5 to about 10 atoms in the ring, in which one or more of the atoms in the ring they are a different element of carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heterocyclenyl contain from about 5 to about 6 ring atoms and 1-3 double bonds. Preferred heterocyclenyl also contain at least one -C = N as part of the ring. The "heterocyclenyl" may be optionally substituted with one or more "ring system substituents" that may be the same or different, and are as defined herein. The prefix aza, oxa or aunt before the root name of the heterocyclynyl means that at least one nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom. The nitrogen or sulfur atom of the heteroaryl can optionally be oxidized to give the corresponding N-oxide, S-oxide or S, S-dioxide. Non-limiting examples of suitable heterocyclenyl include dihydroimidazole, dihydrooxazole, dihydrooxadiazole, dihydrotiazole and the like.

"Heterocyclyl" (or heterocycloalkyl) means a saturated or non-aromatic monocyclic or multicyclic ring system, comprising from about 3 to about 10 atoms in the ring, preferably from about 5 to about 10 atoms in the ring, in which one or more of the atoms in the ring system is a non-carbon element, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heterocyclyls contain from about 5 to about 6 ring atoms. The prefix aza, oxa

or aunt before the name heterocyclyl root means that at least one nitrogen, oxygen or sulfur atom is present, respectively, as a ring atom. The heterocyclyl may be optionally substituted with one or more "ring system substituents" that may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to give the corresponding N-oxide, S-oxide or S, S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl; oxazolidinyl, imidazolidinyl, thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl and the like. Also included are ring systems comprising from about 3 to about 10 atoms in the ring, preferably from about 5 to about 10 atoms in the ring, in which one or more of the atoms in the ring system is an element other than carbon, for example a nitrogen, oxygen or sulfur atom, alone or in combination, and containing at least one carbon-carbon double bond or carbon-nitrogen double bond. There is no adjacent oxygen and / or sulfur atom present in the ring system. Non-limiting examples of suitable monocyclic (ie, azaheterocyclyl) azaheterocyclic groups include 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 1,4 , 5,6-tetrahydropyrimidine, dihydro-2-pyrrolinyl, dihydro-3-pyrrolinyl, dihydro-2-imidazolinyl, dihydro-2-pyrazolinyl, dihydro-4,5-trizolyl and the like. Non-limiting examples of suitable oxaheterocyclic groups (ie, oxaheterocyclyl) include

3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl and the like. A non-limiting example of a suitable multicyclic oxa-heterocyclic group is 7-oxabicyclo [2,2,1] heptenyl. Non-limiting examples of thiaheterocyclic monocyclic rings (ie, thiaheterocyclyl), include dihydrothiophenyl, dihydrothiopyranyl and the like.

"Heteroaralkyl" means a heteroaryl-alkyl- group, in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyl contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, 2- (furan-3-yl) ethyl and quinolin- (3-yl) methyl. The bond with the parental residue is done through the alkyl.

"Heteroaralkenyl" means a heteroaryl-alkenyl- group, in which the heteroaryl and alkenyl are as previously described. Preferred heteroaralkenyls contain a lower alkenyl group. Non-limiting examples of preferred heteroaralkenyl groups include 2- (pyrid-3-yl) ethenyl and 2- (quinolin-3-yl) ethenyl. The connection with the parental residue is done through the alkenyl.

"Hydroxyalkyl" means an HO-alkyl- group, in which alkyl is as defined above. Preferred hydroxyalkyl contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl. The bond with the parental residue is done through the alkyl.

"Hydroxamate" means an alkyl-C (= O) NH-O- group. The bond with the parental residue is done through the oxygen group.

"Ring system substituent" means a substituent attached to an aromatic or non-aromatic ring system that, for example, replaces a hydrogen available in the ring system. The substituents of the ring system may be the same or different, each independently being selected from the group consisting of H, alkyl, alkenyl, alkynyl, alkoxy, aryl, aroyl, aryloxy, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl, aralkyl, aralkenyl, aralkoxy, aralkoxycarbonyl, amino, -NH (alkyl), -N (alkyl) 2, -NH (cycloalkyl), -N (cycloalkyl) 2, -NH (aryl), -N (aryl) 2, - NH (heteroaryl), -N (heteroaryl) 2, -NH (heterocyclyl), N (heterocyclyl) 2, halo, hydroxy, carboxyl, carboxyalkyl (the example or non-limiting examples include ester), cyano, alkoxycarbonyl, hydroxyalkyl, carbonyl ( the non-limiting example or examples include ketone), -C (= O) heterocyclyl, formyl (the example or non-limiting examples include aldehyde), carboxamido (ie, amido, -C (= O) NH2), -C (= O) N (alkyl) 2, -C (= O) NH (alkyl), -C (= O) N (cycloalkyl) 2, -C (= O) NH (cycloalkyl), alkyl C (= O) NH-, -amidino, hydrazide, hydroxamate, - NHC (= O) H, -NHC (= O) alkyl, urea (for example, -NH (C = O) NH2), -NH (C = O) NH (alkyl), -NH (C = O) NH (alkyl) 2, -NH (C = O) NH (heteroaryl), -NH (C = O) NH (heterocyclyl), guanidinyl, -NHC (= NCN) NH2, -NHC (= NCN) N (alkyl) 2 , carbamoyl (i.e. -CO2NH2), -NHC (= O) Oalkyl, -CO2N (alkyl) 2, -NHC (= O) NH-S (O) 2alkyl, -NHC (= O) N (alkyl) 2 -S (O) 2alkyl, -NH-S (O) 2alkyl, -NH-S (O) 2heteroaryl, -N (alkyl) -S (O) 2alkyl, -NH-S (O) 2aryl, -N (alkyl ) -S (O) 2-aryl, -NH-S (O) 2NH2, -NH-S (O) 2NHalkyl, -NH-S (O) 2N (alkyl) 2, thio, alkylthiocarboxy, -S (O) 2alkyl, -S (O) 2aryl, -OS (O) 2alkyl, -OS (O) 2aryl, sulfonyl urea (the non-limiting example or examples include -NHC (= S) NHalkyl) and OSi (alkyl) 3.

"Spiroalkyl" means an alkylene group in which two carbon atoms of an alkyl group are attached to a carbon atom of a precursor molecular group, thus forming a carbocyclic or heterocyclic ring of three to eleven atoms. Representative structures include examples, such as:

The spiroalkyl groups of the present invention may be optionally substituted with one or more substituents of the ring system, in which the "ring system substituent" is as defined herein.

"Ring system substituent" also means a cyclic ring of 3 to 7 ring atoms, which may contain 1 or 2 heteroatoms, attached to an aryl, heteroaryl or heterocyclyl ring, by simultaneously replacing two atoms of the hydrogen ring in said aryl, heteroaryl, heterocyclyl ring. Non-limiting examples include:

and the like

The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties, at an available position or positions.

With reference to the number of moieties (the non-limiting example or examples include substituents, groups or rings) in a compound, unless otherwise indicated, the phrases "one or more" and "at least one" mean that, it may there are as many remains as chemically allowed, and the determination of the maximum number of said remains falls within the knowledge of those skilled in the art. Preferably, there are one to three substituents, or more preferably, one to two substituents, with at least one in the para position.

10 As used herein, the term "composition" is intended to include a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from the combination of the specified ingredients in the specified amounts. .

The solid line - as a bond, generally indicates a mixture of, or both of, the possible isomers, non-limiting examples include those containing stereochemistry (R) and (S). For example,

means it contains

A dotted line (---) represents an optional link. Lines drawn on ring systems, such as, for example:

indicate that the indicated line (link) can be attached to any of the suitable atoms in the ring, non-limiting examples include carbon, nitrogen and sulfur atoms in the ring.

As is well known in the art, a bond drawn from a particular atom, in which no residue is represented at the terminal end of the bond, indicates a methyl group linked through that bond to the atom, at least 25 otherwise indicated. For example:

It represents

It should be appreciated that any heteroatom with valences not met in the text, schemes, examples, structural formulas and any of the Tables herein is assumed to have the hydrogen atom or atoms to satisfy the valences.

Also contemplated herein are prodrugs and solvates of the compounds of the invention. The term "prodrug," as used herein, represents a compound that is a drug precursor that, after administration to a subject, undergoes chemical conversion by chemical or metabolic processes to produce a compound of Formula 1 or a salt and / or a solvate thereof. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) Volume 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, both are incorporated herein by reference to them.

"Metabolic conjugates", for example, glucuronides and sulfates that may undergo reversible conversion to give compounds of Formula 1 are contemplated in the present application.

"Effective amount" or "therapeutically effective amount" is intended to describe an amount of a compound or a composition of the present invention effective to antagonize CXCR3 and therefore produce the desired therapeutic effect in a suitable patient.

"Mammalian" means humans and other mammalian animals.

"Patient" includes humans and animals.

"Solvate" means a physical association of a compound of the present invention with one or more solvent molecules. Physical association involves varying degrees of ionic or covalent bonding, including hydrogen bonding. In certain cases the solvate will have the capacity for isolation, for example when one or more solvent molecules are incorporated into the crystalline network of the crystalline solid. "Solvato" covers insulated solvates and in solution phase. Non-limiting examples of suitable solvates include ethanolates, methanolates and the like. "Hydrate" is a solvate, in which the solvent molecule is H2O. In general, solvated forms are equivalent to unvavated forms and are intended to be included within the scope of the present invention.

The compounds of Formula 1 form salts that are also within the scope of the present invention. Reference to a compound of Formula 1 herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt (or salts)", as used herein, represents acidic salts formed with inorganic and / or organic acids, as well as basic salts formed with inorganic and / or organic bases. In addition, when a compound of Formula 1 contains a basic moiety, such as, but not limited to, a pyridine or imidazole, and an acidic moiety, such as, but not limited to, a carboxylic acid, zwitterions ("internal salts") may be formed. and are included within the term "salt (or salts)" as used herein. Pharmaceutically acceptable salts are preferred (the non-limiting example or examples include non-toxic, physiologically acceptable), although other salts are also useful. Salts of the compounds of Formula 1 can be formed, for example, by reacting a compound of Formula 1 with an amount of acid or base, such as an equivalent amount, in a medium, such as one in which the salt precipitates or in an aqueous medium followed by lyophilization. Acids (and bases) are disclosed which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds (or acids), for example, by S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66 ( 1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217;

Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; in The Orange Book (Food & Drug Administration, Washington, D.C. or its web pages); and P. Heinrich Stahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (2002) Int'l. Union of Pure and Applied Chemistry, pp. 330-331. These disclosures are incorporated herein by reference to them.

Exemplary acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, canforates, camphorsulfonates, cyclopentane propionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheatoses, glucoheatoses, glucoheatoses, glucoheatoses, glucoheatoses, glucoheatoses, glucoheatoses, glucoheatosites, glucoheatosites, glucoheatosites, glucoheatoses, heptane , hexanoates, hydrochlorides, hydrobromides, iohydrates, 2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates, methyl sulfates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates, pictates, phosphates, pictates, phosphates, salts , succinates, sulfates, sulphonates (such as those mentioned herein), tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) undecanoates and the like.

Exemplary basic salts include ammonium salts, alkali metal salts, such as sodium, lithium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, aluminum salts, zinc salts, salts with organic bases (by eg, organic amines) such as benzathines, diethylamine, dicyclohexylamines, hydrabamines (formed with N, N-bis (dehydroabiethyl) ethylenediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-butylamines, piperazine, phenylcyclohexylamine, choline, tromethamine and salts with amino acids, such as arginine, lysine and the like. The groups containing basic nitrogen can be quaternized with agents, such as lower alkyl halides (the example or non-limiting examples include chlorides, bromides and iodides of methyl, ethyl, propyl and butyl), dialkyl sulfates (the example or non-limiting examples include dimethyl, diethyl, dibutyl and diamyl sulfates), long chain halides (the example or non-limiting examples include chlorides, bromides and iodides of decyl, lauryl, myristyl and stearyl), aralkyl halides (the example or non-limiting examples include benzyl and phenethyl bromides) and others.

All such salts of acids and salts of bases are intended to be pharmaceutically acceptable salts within the scope of the invention and all salts of acids and bases are considered equivalent to the free forms of the corresponding compounds for the purposes of the invention.

Pharmaceutically acceptable esters of the compounds of the present invention include the following groups: (1) carboxylic acid esters obtained by esterification of the hydroxy groups, the non-carbonyl moiety of the carboxylic acid portion of the steric group is selected from alkyl of straight or branched chain (for example, acetyl, n-propyl, t-butyl or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for eg, phenyl optionally substituted with, for example, halogen, C1-4 alkyl or C1-4 alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (eg, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucil); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. Phosphate esters can be further esterified by, for example, a C1-20 alcohol

or reactive derivative thereof, or by a 2,3-diacyl (C6-24) -glycerol.

There may be compounds of Formula 1, and salts, solvates, esters and prodrugs thereof, in their tautomeric forms (for example, as an amide or imino ether). All of these tautomeric forms are contemplated herein as part of the present invention.

All stereoisomers (for example, geometric isomers, optical isomers and the like) of the compounds of the present invention (including those of the salts, solvates, esters and prodrugs of the compounds, as well as the salts, solvates and esters of the prodrugs) , such as those that may exist thanks to asymmetric carbons in various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotamerican forms, atropisomers and diastereomeric forms, are included within the scope of the present invention. The individual stereoisomers of the compounds of the invention may be, for example, substantially free of other isomers, or they may be mixed, for example, in the form of racemates or with all others, or other selected stereoisomers. The chiral centers of the present invention may have the S or R configuration as defined by the IUPAC Recommendations of 1974. The use of terms "salt", "solvate", "prodrug" and the like is intended to apply equally to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the compounds of the invention.

It should also be appreciated that throughout the specification and the claims attached herein, any formula, compound, moiety or chemical illustration with unmet valences, is assumed to have the hydrogen atom to satisfy the valencies, unless The context indicates a link.

In one embodiment, the present invention discloses compounds of Formula 1, which have CXCR3 antagonist activity, or a pharmaceutically acceptable derivative thereof, in which the various definitions have been provided above.

In another embodiment, L is O (i.e. oxygen).

In another embodiment, G is R2R1X-C (R14) (R1S) -.

In another embodiment, where G is R2R1X-C (R14) (R1S) -, X is N, and R14 and R15 taken together are = O.

In another embodiment, where G is R2R1X-C (R14) (R1S) -, X is N, and R14 and R15 taken together are = O, R1 and R2 are both H; that is, R2R1X-C (R14) (R1S) - is H2N- (C = O) -. In another embodiment, G is selected from the group consisting of H, hydroxyl, alkylO- or R2R1N. In another embodiment G is a 5-membered heteroaryl or heterocyclynyl ring containing at least one moiety -C = N

as part of said heteroaryl or heterocyclynyl ring, selected from the group consisting of dihydroimidazole, imidazole, dihydrooxazole, oxazole, dihydrooxadiazole, oxadiazole, triazole and tetrazole. In another embodiment, G is

R3 is selected from the group consisting of H, -Cl and -CH3.

In another embodiment, R8 is selected from the group consisting of H, alkyl, alkenyl, arylalkyl, cycloalkyl, - (CH2) qOH, - (CH2) qOR31, - (CH2) qNH2, - (CH2) qNHR31, - (CH2 ) qC (= O) NHR31, - (CH2) qSO2R31, - (CH2) qNSO2R31 and - (CH2) qSO2NHR31.

The R9 residues may be the same or different, each independently selected from the group that

It consists of -NH2 and -N (H) CH2CH3.

R10 is selected from the group consisting of -CH3, -CH2CH3 and -CH2CH2CH3, and m is 0-2.

In another embodiment, R10 is -CH2CH3 and m is 1.

R11 is H or -CH3.

In another embodiment, R11 is H.

R12 is H.

Ring D is selected from phenyl and pyridinyl.

The R20 moieties may be the same or different, each independently selected from the group that

It consists of H, halogen and amino. And it is selected from the group consisting of: -CH2- and -C (= O) -. m is 0-2. In another embodiment, m is 1. In another embodiment, n is 0-2. In another embodiment, n is 0. In another embodiment, q is 1 or 2. In another embodiment, G is independently selected from the group consisting of R2R1N-C (= O) - and

R9 is selected from the group consisting of -NH2 and -N (H) CH2CH3;

R10 is -CH2CH3;

R11 is H;

R12 is H; 5 ring D is selected from phenyl and pyridinyl

R20 residues may be the same or different, each independently selected from the group that consists of H, halogen and amino; And it is selected from the group consisting of: -CH2- and -C (= O) -; m is 1; Y

10 n is 0. In another embodiment, the compound of Formula 1 is selected from the group consisting of the following:

or a pharmaceutically acceptable salt, solvate or ester thereof.

or a pharmaceutically acceptable salt, solvate or ester thereof.

In another embodiment, the compound is selected from the group consisting of

In yet another embodiment of the present invention, a compound is selected from the following structures in the

5 Table 1 below (or pharmaceutically acceptable salts, solvates or esters thereof) shown together with their Ki classifications. Ki values are classified, "A" for Ki values below approximately 25 nanomolar (nM), "B" for Ki values in the range of approximately 25 to approximately 100 nM, and "C" for Ki values greater than approximately 100 nM. For example, Compound Number 1 has a Ki of 1.9 nM, and therefore has a rating of "A".

10 Table 1

Compound Number

 STRUCTURE  Ki classification

one

TO

(Continuation)

Compound Number

 STRUCTURE  Ki classification

2

TO

3

TO

4

TO

5

TO

6

B

7

B

(Continued) Examples of representative compounds with specific Ki values are set forth below in Table 2:

Compound Number

 STRUCTURE  Ki classification

8

B

9

B

10

B

eleven

B

12

C

Compound Number

STRUCTURE Ki

one

1.9

2

2.6

3

7.5

4

8.3

5

1.9

In yet another aspect, the compound according to Formula 1 is in purified form.

In another embodiment, the present invention provides a pharmaceutical composition comprising at least one compound of Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof in combination with at least one pharmaceutically acceptable carrier.

In yet another embodiment, the invention provides a pharmaceutical composition of Formula 1, which additionally comprises at least one additional agent, drug, medicament, antibody and / or inhibitor for the treatment of

chemokine receptor mediated diseases CXCR3.

When a combination therapy is administered to a patient in need of such administration, the therapeutic agents in the combination or a pharmaceutical composition or compositions comprising the therapeutic agents can be administered in any order, such as, for example, sequentially, at the same time. , together, simultaneously and similarly. The amounts of the various active ingredients in such combination therapy may be different amounts (different dosage amounts) or the same amounts (same dosage amounts). Therefore, for illustrative, non-limiting purposes, a compound of formula III and an additional therapeutic agent may be present in fixed amounts (dosage amounts) in a single dosage unit (eg, a capsule, a tablet and the like). A commercial example of such a simple dosage unit that contains fixed amounts of two different active compounds is VYTORIN® (available from Merck Schering-Plow Pharmaceuticals, Kenilworth, New Jersey).

In a further embodiment, the present invention discloses methods for preparing pharmaceutical compositions comprising, as active ingredient, the heterocyclic substituted piperazine compounds of Formula 1 of the invention. In the pharmaceutical compositions and methods of the present invention, the active ingredients will normally be administered mixed with suitable carrier materials, conveniently selected with respect to the desired administration form, i.e. oral tablets, capsules (with solid, semi-solid or liquid filler ), constitution powders, oral gels, elixirs, dispersible granules, syrups, suspensions and the like and consistent with conventional pharmaceutical practical embodiments. For example, for oral administration in the form of tablets or capsules, the active pharmacological component may be combined with any inert, non-toxic, pharmaceutically acceptable carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, sulfate. calcium, talc, mannitol, ethyl alcohol (liquid forms) and the like. In addition, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated into the mixture. The powders and tablets may comprise from about 5 to about 95 percent of the composition of the invention. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums, such as gum arabic, sodium alginate, carboxymethyl cellulose, polyethylene glycol and waxes. Among the lubricants that may be mentioned for use in these dosage forms, are boric acid, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrants include starch, methyl cellulose, guar gum and the like. Sweetening, flavoring and preservative agents may also be included when appropriate. Some of the terms indicated above, namely disintegrants, diluents, lubricants, binders and the like, are discussed in more detail below.

Additionally, to optimize the therapeutic effects, the compositions of the present invention may be formulated in the form of prolonged release to provide the controlled release rate of any one or more of the active components or principles, ie anti-inflammatory activity and the like. Dosage forms suitable for prolonged release include layered tablets containing layers of various disintegration rates or controlled release polymer matrices impregnated with the active components and formed into tablets or capsules containing such porous polymeric capsules, encapsulated or impregnated. .

Liquid form preparations include solutions, suspensions and emulsions. As an example, water or aqueous propylene glycol solutions for parenteral injections or the addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions can be mentioned. Liquid form preparations may also include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier such as compressed inert gas, for example nitrogen.

For the preparation of suppositories, a low melting wax is first melted, such as a mixture of glyceric fatty acids, such as cocoa butter and the active ingredient is dispersed, homogeneously inside, stirring or mixing in a similar manner . Then, the molten homogeneous mixture is poured into molds of convenient size, allowed to cool and therefore solidify.

Also included are solid form preparations intended to be transformed, shortly before use, into liquid form preparations for oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

The compounds of the invention can also be administered transdermally. The transdermal compositions may be in the form of creams, lotions, aerosols and / or emulsions and may be included in a transdermal patch of matrix or deposit type as is usual in the art for this purpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses of the appropriate size containing appropriate amounts of the active components,

for example, an effective amount to achieve the desired end.

The amount of the active composition of the invention in a unit preparation dose may generally vary or be adjusted from about 1.0 milligrams to about 1,000 milligrams, preferably from about 1.0 to about 950 milligrams, more preferably from about 1.0 to about 500 milligrams, and usually about 1 to about 250 milligrams, according to the particular application. The actual dosage used may vary depending on the age, sex and weight of the patient and the severity of the condition to be treated. Such techniques are well known to those skilled in the art.

Generally, the oral dosage form for humans containing the active substances can be administered 1 or 2 times a day. The amount and frequency of administration will be regulated according to the criteria of the attending physician. A daily dosage regimen generally recommended for oral administration may vary from about 1.0 to about 1000 milligrams per day, in divided or single doses.

Here are some useful terms:

Capsule - refers to a special container or container made of methylcellulose, polyvinyl alcohols or denatured gelatins or starch to store or contain the compositions comprising the active ingredients. Hard shell capsules are normally made with mixtures of bone and pig skin jelly of relatively high gel consistency. The capsule itself may contain small amounts of pigments, opacifying agents, plasticizers and preservatives.

Compressed - refers to a compressed or molded solid dosage form containing the active ingredients with suitable diluents. The tablet can be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation or by compaction.

Oral gels - refers to the active ingredients dispersed or solubilized in a hydrophilic semi-solid matrix.

Powders for constitution - refers to powder mixtures containing the active ingredients and suitable diluents that can be suspended in water or in juices.

Diluent - refers to substances that normally make up the bulk of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol; starches derived from wheat, corn, rice and potatoes; and celluloses such as microcrystalline cellulose. The amount of diluent in the composition may vary from about 10 to about 90% by weight of the total composition, preferably from about 25 to about 75%, more preferably from about 30 to about 60% by weight, even more preferably from about 12 to about 60%.

Disintegrants - refer to materials added to the composition to aid in their separation (disintegration) and release the medications. Suitable disintegrants include starches; modified "cold water soluble" starches such as carboxymethyl sodium starch, natural and synthetic gums such as locust bean gum, karayá, guaro, tragacanth and agar; cellulose derivatives such as methyl cellulose and sodium carboxymethyl cellulose; microcrystalline celluloses and crosslinked microcrystalline celluloses, such as croscarmellose sodium; alginates such as alginic acid and sodium alginate; clays such as bentonites; and effervescent mixtures. The amount of disintegrant in the composition may vary from about 2 to about 15% by weight of the composition, more preferably from about 4 to about 10% by weight.

Binders - refers to substances that bind or "stick" powders together and make them cohesive forming granules, thus serving as the "adhesive" in the formulation. The binders add cohesive strength already available in the diluent or volume forming agent. Suitable binders include sugars such as sucrose; starches derived from wheat, corn, rice and potatoes; natural gums such as gum arabic, gelatin and tragacanth, seaweed derivatives such as alginic acid, sodium alginate and calcium and ammonium alginate; cellulosic materials such as methylcellulose and sodium carboxymethylcellulose and hydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganic such as magnesium aluminum silicate. The amount of binder in the composition may vary from about 2 to about 20% by weight of the composition, more preferably from about 3 to about 10% by weight, even more preferably from about 3 to about 6% in weigh.

Lubricant - refers to a substance added to the dosage form to allow the tablet, granules, etc., after being compressed, to be released from the mold or matrix reducing friction or wear. Suitable lubricants include metal stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; high melting point waxes; and water soluble lubricants, such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and d’l-leucine. Lubricants are usually added in the last stage before compression, as they must be present on the surfaces of the granules and between them and the parts of the tablet press. The amount of lubricant in the composition may vary from about 0.2 to about 5% by weight of the composition, preferably from

about 0.5 to about 2%, more preferably about 0.3 to about 1.5% by weight.

Emollients - refers to materials that prevent caking and improve the flow characteristics of the granulations, so that the flow is smooth and uniform. Suitable emollients include silicon dioxide and talc. The amount of emollient in the composition may vary from about 0.1% to about 5% by weight of the total composition, preferably from about 0.5 to about 2% by weight.

Coloring agents - refers to excipients that provide color to the composition or dosage form. Such excipients may include food use pigments and food use pigments adsorbed onto a suitable adsorbent such as clay or aluminum oxide. The amount of coloring agent may vary from about 0.1 to about 5% by weight of the composition, preferably from about 0.1 to about 1%.

Bioavailability - refers to the speed and degree to which the active pharmacological principle or therapeutic moiety is absorbed into the systemic circulation from a dosage form administered compared to a standard or control. Conventional methods for the preparation of tablets are known. Such procedures include dry procedures such as direct compression and granulation compression produced by compaction, or wet procedures or other special procedures. Conventional methods for manufacturing other forms of administration such as, for example, capsules, suppositories and the like are well known.

It will be apparent to those skilled in the art that many modifications, variations and alterations can be made with respect to the present disclosure, both in terms of materials and procedures. Such modifications, variations and alterations are intended to be included within the spirit and scope of the present invention.

As mentioned above, the invention also includes tautomers, enantiomers and other stereoisomers of the compounds. Therefore, as one skilled in the art knows, certain imidazole compounds may exist in tautomeric forms. It is contemplated that such variations are within the scope of the present invention. Some compounds of the present invention may exist in multiple crystalline forms or in amorphous forms. All physical forms of the present invention are contemplated.

Compounds of the invention are contemplated in the present invention that contain unnatural proportions of atomic isotopes (ie, "radiolabeled compounds") whether their use is therapeutic, for diagnosis or as a research reagent.

Another embodiment of the present invention discloses the use of the pharmaceutical compositions described above for the treatment of diseases of a disease mediated by the CXCR3 chemokine receptor, in a patient in need of such treatment, which comprises administering to the patient a therapeutically effective amount of less a compound according to Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof.

In another embodiment, the method refers to administering to the patient (a) an effective amount of at least one compound according to Formula 1, or a pharmaceutically acceptable salt, unsolvate or ester thereof simultaneously or sequentially with (b) at least one additional agent, drug, medicament, antibody and / or inhibitor for the treatment of a disease mediated by the CXCR3 chemokine receptor, in combination with a pharmaceutically acceptable carrier.

In another embodiment, at least one compound of Formula 1 binds to a CXCR3 receptor.

The process may further comprise administering: (a) a therapeutically effective amount of at least one compound according to Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof simultaneously or sequentially with (b) at least a drug selected from the group consisting of: disease modifying antirheumatic drugs; non-steroidal anti-inflammatory drugs; selective COX-2 inhibitors; COX-1 inhibitors; immunosuppressants (non-limiting examples include methotrexate, cyclosporine, FK506); steroids; PDE IV inhibitors, anti-TNF-α compounds, TNF-alpha-convertase inhibitors, cytokine inhibitors, MMP inhibitors, glucocorticoids, chemokine inhibitors, selective CB2 inhibitors, p38 inhibitors, biological response modifiers; anti-inflammatory and therapeutic agents. The disease can be an inflammatory disease.

Another embodiment of the present invention relates to a compound according to Formula 1, for use in a method of inhibiting or blocking T-lymphocyte-mediated chemotaxis in a patient in need of such treatment, the procedure comprising administering to the patient a quantity therapeutically effective of at least one compound according to Formula 1 or a pharmaceutically acceptable salt, solvate or ester thereof.

Another embodiment of the present invention relates to a compound according to Formula 1, for use in a

A method for the treatment of an inflammatory bowel disease in a patient who needs such treatment which comprises administering to the patient a therapeutically effective amount of at least one compound according to Formula 1 or a pharmaceutically acceptable salt, solvate or ester thereof.

Another embodiment of the present invention relates to a compound according to formula 1, for use in a procedure for the treatment or prevention of graft rejection in a patient in need of such treatment which comprises administering to the patient a therapeutically effective amount. of at least one compound according to Formula 1 or a pharmaceutically acceptable salt, solvate or ester thereof.

Another embodiment of the present invention relates to a compound according to formula 1, for use in a method comprising administering to the patient a therapeutically effective amount of: (a) at least one compound according to Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof, simultaneously or sequentially with (b) at least one compound selected from the group consisting of: cyclosporin A, FK-506, FTY720, beta-interferon, rapamycin, mycophenolate, prednisolone, azathioprine, cyclophosphamide and antilymphocyte globulin.

Another embodiment of the present invention relates to a compound according to formula 1, for use in a procedure for the treatment of multiple sclerosis in a patient in need of such treatment, the procedure comprising administering to the patient a therapeutically effective amount of: ( a) at least one compound according to Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof, simultaneously or sequentially with (b) at least one compound selected from the group consisting of: beta-interferon , glatiramer acetate, glucocorticoids, methotrexate, azothioprine, mitoxantrone, VLA-4 inhibitors and / or selective CB2 inhibitors.

Another embodiment of the present invention relates to a compound according to formula 1, for use in a method for the treatment of multiple sclerosis in a patient in need of such treatment comprising administering to the patient a therapeutically effective amount of: (a ) at least one compound according to Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof, simultaneously or sequentially with (b) at least one compound selected from the group consisting of: methotrexate, cyclosporine, leflunimide, sulfasalazine, β-metasona, β-interferon, glatiramer acetate, prednisone, etonercept and infliximab.

Another embodiment of the present invention relates to a compound according to formula 1, for use in a procedure for the treatment of rheumatoid arthritis in a patient in need of such treatment, the procedure comprising administering to the patient a therapeutically effective amount of: ( a) at least one compound according to Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof, simultaneously or sequentially with (b) at least one compound selected from the group consisting of: COX inhibitors -2, COX inhibitors, immunosuppressants, steroids, PDE IV inhibitors, anti-TNF-α compounds, MMP inhibitors, glucocorticoids, chemokine inhibitors, selective CB2 inhibitors, caspase inhibitors (ICE) and other classes of compounds indicated for the treatment of rheumatoid arthritis.

Another embodiment of the present invention relates to a compound according to formula 1, for use in a procedure for the treatment of psoriasis in a patient in need of such treatment, the procedure comprising administering to the patient a therapeutically effective amount of: (a ) at least one compound according to Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof, simultaneously or sequentially with (b) at least one compound selected from the group consisting of: immunosuppressants, steroids and anti-TNF-α compounds.

Another embodiment of the present invention relates to a compound according to formula 1, for use in a method for the treatment of a disease selected from the group consisting of: inflammatory disease, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, graft rejection, psoriasis, drug-fixed rashes, delayed skin hypersensitivity responses, tuberculoid leprosy, type I diabetes, viral meningitis and tumors in a patient in need of such treatment, said procedure comprising administering to the patient an effective amount of at less a compound according to Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof.

Another embodiment of the present invention relates to a compound according to formula 1, for use in a method for the treatment of a disease selected from the group consisting of: inflammatory disease, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, graft rejection, psoriasis, drug-fixed rashes, delayed skin hypersensitivity responses, tuberculoid leprosy and cancer, in a patient in need of such treatment, said procedure comprising administering to the patient an effective amount of at least one compound according to the Formula 1, or a pharmaceutically acceptable salt, solvate or ester thereof.

Another embodiment of the present invention relates to a compound according to formula 1, for use in a method for the treatment of a disease selected from the group consisting of: inflammatory disease, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, graft rejection, psoriasis, drug-fixed rashes, delayed skin hypersensitivity responses and tuberculoid leprosy,

type I diabetes, viral meningitis and cancer in a patient in need of such treatment, said procedure comprising administering to the patient an effective amount of (a) at least one compound according to Formula 1,

or a pharmaceutically acceptable salt, solvate or ester thereof, simultaneously or sequentially with (b) at least one drug selected from the group consisting of: disease-modifying anti-rheumatic drugs; non-steroidal anti-inflammatory drugs; selective COX-2 inhibitors, COX-1 inhibitors; immunosuppressants, steroids, PDE IV inhibitors, anti-TNF-α compounds, MMP inhibitors, glucocorticoids, chemokine inhibitors, selective CB2 inhibitors, biological response modifiers and anti-inflammatory agents and therapeutic compounds.

Another embodiment of the present invention discloses a process for manufacturing the substituted pyrazine compounds disclosed above.

Unless otherwise indicated, the following abbreviations have the meanings indicated, in the following Examples:

DBU = 1,8-diazabicyclo [5,4,0] undec-7-eno

DBN = 1,5-diazabicyclo [4,3,0] non-5-eno

DMF = N, N-dimethylformamide

Et2O = diethyl ether

EDCI = 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide

HOBT = 1-hydroxybenzotriazole

DCC = dicyclohexylcarbodiimide

Dibal-H = diisobutylaluminum hydride

LAH = lithium aluminum hydride

NaBH (OAc) 3 = sodium triacetoxyborohydride

NaBH4 = sodium borohydride

NaBH3CN = sodium cyanoborohydride

LDA = lithium diisopropylamide

p-TsOH = p-toluenesulfonic acid

m-CPBA = m-Chloroperbenzoic Acid

TMAD = N, N, N ', N'-tetramethylazodicarboxamide

CSA = camphorsulfonic acid

NaHMDS = sodium hexamethyl disililazide

THF = tetrahydrofuran

HRMS = High Resolution Mass Spectrometry

HPLC = High pressure liquid chromatography

LRMS = Low Resolution Mass Spectrometry

nM = nanomolar

Ki = Dissociation constant for substrate / receptor complex

pA2 = -logEC50, as defined by J. Hey, Eur. J. Pharmacol., (1995), Vol. 294, 329-335.

Ci / mmol = Curie / mmol (a measure of specific activity)

Tr = Triphenylmethyl

TRIS = Tris (hydroxymethyl) aminomethane

GENERAL SYNTHESIS

The compounds of the present invention can be prepared in a variety of ways evident to one skilled in the art. Preferred procedures include, but are not limited to, the general synthetic procedures described herein. One skilled in the art will recognize that a route will be optimal depending on the choice of complementary substituents. In addition, one skilled in the art will recognize that in some cases the order of the stages has to be controlled to avoid incompatibilities of functional groups. One skilled in the art will recognize that a more convergent route (ie, nonlinear or preassembly of certain portions of the molecule) is a more efficient method of assembling the target compounds. Process for the preparation of compounds of the general formula 1, in which the variables (R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R30, R31, G, L, Z, X, D, Y, m, n, pyq) are as defined above, are shown in Schemes 1, 2 and 3. Pr1, Pr2 and Pr3 are protective groups that are further illustrated ahead.

The starting materials and reagents used in the preparation of the described compounds are available from commercial suppliers, such as Aldrich Chemical Co. (Wisconsin, United States) and Acros Organics Co. (New Jersey, United States) or known bibliographic procedures were prepared for experts in the field.

The preparation of arylpiperazine compounds related to intermediate III has been described in WO-03037862 (Nippon Shinyaku).

One skilled in the art will recognize that the synthesis of compounds of formula 1 may require the need for protection of certain functional groups (ie derivatization for the purpose of chemical compatibility with a particular reaction condition). A suitable protecting group for a carboxylic acid (Pr1, when R14, R15 = O) the methyl, ethyl,

10 isopropyl or benzyl ester and the like. A suitable protecting group for an amine (Pr2, Pr3) is methyl, benzyl, ethoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, phthaloyl, trifluoroacetyl, acetyl and the like. All protecting groups can be added and removed by bibliographic procedures known to those skilled in the art.

One skilled in the art will recognize that the synthesis of compounds of formula 1 may require the construction of an amide bond. The procedures include, but are not limited to, the use of a reactive carboxyl derivative (for

For example, acid halide, or ester at elevated temperatures) or the use of an acid coupling reagents (eg, EDCI, DCC) in the presence of an amine from 0 ° C to 100 ° C. Suitable solvents for the reaction are halogenated hydrocarbons, ethereal solvents, DMF and the like. The reaction can be carried out under pressure or in a tightly closed container.

One skilled in the art will recognize that the synthesis of compounds of formula 1 may require the construction of a

20 amine bond. One such procedure is, but not limited to, the reaction of a primary or secondary amine with a respective carbonyl (eg, aldehyde or ketone) under conditions of reductive amination. Suitable reducing agents are the intermediate imine NaBH4, NaBH (OAc) 3 and the like, from 0 ° C to 100 ° C. Suitable solvents for the reaction are halogenated hydrocarbons, ethereal solvents, DMF and the like. Optionally, the reaction can be carried out in the presence of titanium tetraisopropoxide to facilitate the generation of imine. Other from

Such procedures are, but are not limited to, the reaction of a primary or secondary amine with a reactive alkylating agent, such as an alkyl halide, benzyl halide, mesylate, tosylate and the like. They are solvents

suitable for the reaction halogenated hydrocarbons, ethereal solvents, DMF and the like. The reaction can be carried out under pressure or in a tightly closed container from 0 ° C to 100 ° C.

One skilled in the art will recognize that the synthesis of compounds of formula 1 may require the reduction of a reducible functional group. Suitable reducing agents include NaBH4, LAH, diborane and the like from -20 ° C to 100 ° C. Suitable solvents for the reaction are halogenated hydrocarbons, ethereal solvents, DMF and the like.

One skilled in the art will recognize that the synthesis of compounds of formula 1 may require the oxidation of a functional group. Suitable oxidation reagents include oxygen, hydrogen peroxide, m-CPBA and the like from -20 ° C to 100 ° C. Suitable solvents for the reaction are halogenated hydrocarbons, ethereal solvents, water and the like.

The starting and intermediate materials of a reaction can be isolated and purified if desired using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

General Description of Procedures

Stage A. Administration of 2-Halopyrazine

A suitably protected 2-halopyrazine of formula I is reacted with a piperazine of formula II to form a compound of the general formula III. Preferably, the reaction is carried out in a solvent, such as dioxane in the presence of a base, such as potassium carbonate or cesium carbonate.

Stage A '. Protection in piperazine amine

Optionally, if the 2-halopyrazine of formula I is reacted with unprotected piperazine II (in which Pr2 = H), the product of formula III needs to be protected with a suitable amine protecting group described above.

Stage B. Sandmyer reaction.

A suitably protected 2-halopyrazine of formula III is reacted with a nitrite alkyl in the presence of acid to form a compound of the general formula IV. Preferably, the reaction is carried out in a solvent, such as THF and water. Alternatively, a fully assembled 6-aminopyrazine of formula XXI is reacted under the same reaction condition described above to provide a compound of general formula XVI

Stage C. N-Alkylation of 2-Pyrazinone

A suitably protected 2-pyrazinone of formula IV is reacted with an alkylating agent, such as methyl iodide to form an N-alkylated product of the general formula V. Preferably, the reaction is carried out in a solvent, such as acetone in presence of a base, such as potassium carbonate or cesium carbonate.

Stage D. Amidation of an Ester

A suitably protected alkyl ester of formula V (when R14, R15 = O) is reacted with an amine to provide an amide of the general formula VI. Preferably, the reaction is carried out in a solvent, such as methanol or dioxane in a pressure vessel of 25 ° C to 100 ° C.

Stage D '. Hydrazide Formation

A suitably protected alkyl ester of formula XIII (when R14, R15 = O) is reacted with a hydrazide (substituted or unsubstituted) to provide a hydrazide of the general formula XIV. Preferably, the reaction is carried out in a polar solvent, such as MeOH or EtOH from 25 ° C to 100 ° C.

Stage E. Deprotection of Amine Protective Group

Optionally, if the product of step A is a protected piperazine of structure III, deprotection is needed. When Pr2 is benzyl or substituted benzyl, deprotection can be effected by reaction at a pressure of hydrogen gas, in the presence of a catalyst, such as palladium. When Pr2 is ethoxycarbonyl, deprotection can be effected by reaction with trimethylsilyl iodide. When Pr2 is t-butoxycarbonyl, deprotection can be effected with a strong acid, such as trifluoroacetic acid.

Stage F. Reductive Amination

A piperazine of structure VII is reacted with a ketone of structure VIII, in the presence of a reducing agent, with or without titanium tetraisopropoxide, to form a compound of structure VIV, wherein R12 is hydrogen. The general conditions for the reductive amination reaction have been described above.

Stage G. Deprotection of Amine Protector Group

Optionally, if the stage F ketone is a protected piperazine of structure VIII, deprotection is needed. When Pr3 is benzyl or substituted benzyl, deprotection can be effected by reaction at a pressure of hydrogen gas, in the presence of a catalyst, such as palladium. When Pr3 is ethoxycarbonyl, deprotection can be effected by reaction with trimethylsilyl iodide. When Pr3 is t-butoxycarbonyl, deprotection can be effected with a strong acid, such as trifluoroacetic acid.

Stage H. Amide formation when Y = C = O

A compound of structure X is reacted with reactive carboxyl derivatives (acid halide or ester)

or the corresponding acids under general conditions described above.

Stage H. Amine formation when Y = CR1 R2

A compound of structure X is reacted with reactive carbonyl derivatives (aldehyde or ketone) under the reductive amination condition described above. Other procedures include the use of alkylating agents, such as alkyl halide, benzyl halide, mesylate, tosylate or the like. The general conditions described above.

Stage H '.

Optionally, manipulation of a functional group of a compound of structure XI or XVI can be performed to provide additional related compounds of structure XI or XVI.

Stage I. Suzuki Coupling

A suitably protected ester of formula XIII, wherein R14 = R15 = O and R3 = Cl, is reacted with an alkylboronic acid, in the presence of a suitable palladium catalyst and ligands under typical Suzuki coupling conditions. Preferably, the reaction is carried out in a solvent, such as DMF or THF, in the presence of a base, such as potassium carbonate or sodium carbonate from 25 ° C to 100 ° C.

Stage J. Formation of rest of Heterocycle

A suitably protected hydrazide of formula XIV, wherein R14 = R15 = O and Pr3 is an amine protecting group described above, is reacted with an acylation reagent to provide a heterocycle in the presence of a dehydration agent, such as chloride of p-toluenesulfonyl. Normally, the reaction is carried out in a solvent, such as THF or acetonitrile from 25 ° C to 100 ° C.

The compounds of formula 1 can be prepared by the general procedures indicated in Schemes 1, 2 and 3. Syntheses of the compounds specifically illustrated were prepared as described in detail below. The following EXAMPLES have been provided to further illustrate the present invention. These are for illustrative purposes only; The scope of the invention should not be considered limited in any way by them.

Examples

Example 1, Stage A, Procedure A

A round bottom flask was charged with methyl 6-amino 2,3-dichloro pyrazine-5-carboxylate (Aldrich, 25 g, 112.6 mmol), 2-S-ethyl piperazine (prepared as by Williams et al., J. Med. Chem 1996, 39, 1345, 83% active, 15.7 g, 112.7 mmol), cesium carbonate (100 g, 300 mmol) and 1.4 dioxane (400 ml). The flask was equipped with a reflux condenser and heated to 80 ° C. After 12 hours, the reaction was cooled, diluted with CH2Cl2 (~ 200 ml) and filtered through Celite. The filtrate was washed once with water and then concentrated to give an oil. The crude product was purified by column chromatography on silica gel (3% to 10% MeOH in CH2Cl2) to afford compound A3 (30.8 g, 91%). MS: M + H = 300

Example 2, Step A ', Procedure A A solution of A3 (19 g, 63 mmol) and triethylamine (26 ml, 189 mmol) in CH2Cl2 (300 ml) was treated with trifluoroacetic anhydride (13 ml, 94 mmol) at 0 ° C . The reaction mixture was stirred for 16 hours at 0 ° C to 25 ° C. The reaction mixture was treated with an aqueous solution of NaHCO3 and stirred for a further 10 hours at 25 ° C. The organic phases were extracted with CH2Cl2 and the combined organic solution was washed with a brine solution, dried (Na2SO4) and concentrated in vacuo. The crude product A4 (24.9 g, 100%) was pure enough for use in the next step without further purification. MS: M + H = 396

Example 3, Stage B, Procedure A

A cold suspension of A4 (3.09 g, 7.8 mmol) in THF (78 ml) was treated with a 50% aqueous solution of H2SO4 (5 ml) and t-butyl nitrite (5 ml). The reaction mixture was stirred for 1 hour at 0 ° C. The reaction mixture was added to a mixture of CH2Cl2 and an aqueous solution of NaHCO3. The mixture was stirred for 0.5 hours and the organic phases were extracted with CH2Cl2. The combined organic solution was washed with a brine solution, dried (Na2SO4) and

15 concentrated in vacuo. The crude product of formula B1 (3 g, 95%) was used for the next step without further purification. MS: M + H = 395

Example 4, Stage C, Procedure A

A mixture of B1 (3 g, 7.8 mmol), cesium carbonate (5 g, 15.3 mmol) and methyl iodide (1.2 ml, 19.2 mmol) in acetone (180 ml) was stirred at 70 ° C for 20 hours. The mixture was concentrated and the residue was dissolved in CH2Cl2. The organic solution was washed with water and a brine solution, dried (Na2SO4) and concentrated in vacuo to give the crude product of formula C1 (3.2 g, 100%). MS: M + H = 411.

25 Example 5, Stage D, Procedure A

A solution of C1 (238 mg, 0.58 mmol) in CH2Cl2 (3 ml) was treated with 7 N NH3 in MeOH (1 ml) at 25 ° C. The reaction mixture was stirred for 4.5 hours at that temperature and then concentrated in vacuo. The residue was dissolved in 7 N NH3 in MeOH (5 ml) and the solution was stirred for 17 hours. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (1.5% NH3 7 N -OH in CH2Cl2) to provide a compound of formula E1 (140 mg, 81%). MS: M + H = 299.

Example 6, Stage F, Procedure A

A solution of E1 (138 mg, 0.46 mmol) and N-Boc-4-piperidone (137 mg, 0.69 mmol) in 1,2-dichloroethane (4 ml) was treated with NaBH (OAc) 3 (292 mg, 1.38 mmol) at 25 ° C. The reaction mixture was stirred at 60 ° C for 16 hours. To the mixture was added more NaBH (OAC) 3 (60 mg, 0.28 mmol) and the reaction mixture was continued under stirring at 60 ° C for 3 hours. The reaction mixture was cooled and added to an aqueous solution of NaHCO3. The organic phases were extracted with EtOAc and the combined organic solution was washed with a brine solution, dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (2.5% MeOH in CH2Cl2) to provide F1 (105 mg, 47%). MS: M + H = 483.

Example 7, Stage G, Procedure A

A solution of F1 (92 mg, 0.19 mmol) in CH2Cl2 (2 ml) was treated with trifluoroacetic acid (0.2 ml) at 0 ° C. The reaction mixture was stirred for 3 hours at 0 ° C to 25 ° C. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (2.5% to 10% NH3-MeOH in CH2Cl2) to provide G1 (35 mg, 48%). MS: M + H = 383.

Example 8, Stage H, Procedure A

A solution of G1 (35 mg, 0.091 mmol) in DMF (1 ml) was treated with lithium 2-amino-6-chloronicotinate (19.6 mg, 0.11 mmol, preparation: see below), hydrochloride 1 - [3- (dimethylamino) propyl] -3-ethylcarbodiimide (EDCI, 35 mg, 0.18 mmol) and 1-hydroxybenzotriazole (HOBt, 37 mg, 0.27 mmol) at 25 ° C. The reaction mixture was stirred for 24 hours at that temperature and added to an aqueous solution of NaHCO3. The mixture was stirred for 2 hours and the organic phases were extracted with EtOAc. The combined organic solution was washed with a brine solution, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography (1.5% NH3-N3-MeOH in CH2Cl2), to give H1 (26 mg, 55%). MS: M + H = 520.

Example 9, Stage E ', Procedure B

A solution of C1 (1.03 g, 2.5 mmol) in MeOH (70 ml) and water (20 ml) was treated with NaBH4 (226 mg, 5.95 mmol, added as 4 portions for 23 hours) at 25 ° C. The reaction mixture was stirred for 24 hours at 25 ° C.

5 and was quenched by the addition of a saturated aqueous solution of NaHCO3 (20 ml). The mixture was stirred for 1 hour at 25 ° C. The organic solvent was removed by evaporation. The aqueous solution was extracted with EtOAc and the combined organic solution was washed with a brine solution, dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (3% to 5% MeOH in CH2Cl2), providing E2 (496 mg, 63%).

10 MS: M + H = 315.

Example 10, Stage I ', Procedure B

A mixture of F2 (161 mg, 0.32 mmol), methylboronic acid (30 mg, 0.49 mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropaladium (II), complex with dichloromethane (1: 1 ) (52 mg, 0.064 mmol) and carbonate

Potassium (89 mg, 0.64 mmol) in DMF (2 ml) was degassed and stirred at 70 ° C for 20 hours. The reaction mixture was cooled and added to an aqueous solution of NaHCO3. The organic phases were extracted with EtOAc and the combined organic solution was washed with a brine solution, dried (Na2SO4) and concentrated in vacuo. The residue was purified preparative TLC (10% MeOH in CH2Cl2), providing 11 (115 mg, 75%). MS: M + H = 478.

20 Example 11, Stage D ', Procedure B

A compound of the structure of I1 (107 mg, 0.22 mmol) in EtOH (4 ml) was treated with hydrazine (70 µl, 2.2 mmol) and the reaction mixture was stirred at 60 ° C for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (2.5% to 5% MeOH in CH2Cl2) to provide D1 (64.2 mg, 60

25%) MS: M + H = 478.

Example 12, Stage J, Procedure B

A solution of compound D1 (65 mg, 0.135 mmol) in CH2Cl2 (2 mL) was treated with ethyl isocyanate (13 µl, 0.163 mmol) at 0 ° C. The reaction mixture was stirred at 25 ° C for 1 hour. The reaction mixture was treated with triethylamine.

5 (94 ml, 0.675 mmol) and p-toluenesulfonyl chloride (31 mg, 0.162 mmol) at 25 C and the mixture was stirred for 20 hours. The reaction mixture was added to an aqueous solution of NaHCO3 and the organic solution was extracted with CH2Cl2. The combined organic solution was washed with a brine solution, dried (Na2SO4), and concentrated in vacuo. The residue was purified by preparative TLC (10% MeOH in CH2Cl2) to provide J1 (26 mg, 36%). MS: M + H = 531.

10 Example 13, Stage H ", Procedure B

A solution of compound J1 (26 mg, 0.049 mmol) in CH2Cl2 (1 ml) was treated with trifluoroacetic acid (0.1 ml) at 25

ºC. The reaction mixture was stirred at that temperature for 1 hour. The reaction mixture was concentrated in vacuo and the

Residual material was dissolved in DMF (0.6 ml). The solution was treated with triethylamine (20 ml, 0.14 mmol) and the mixture was stirred for 0.25 hours before the addition of lithium 2-amino-6-chloronicotinate (10.5 mg, 0.06 mmol , preparation:

see below), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (EDCI, 19 mg, 0.1 mmol) and

1-hydroxybenzotriazole (HOBt, 20 mg, 0.15 mmol) at 25 ° C. The reaction mixture was stirred for 7 hours at 25 ° C. The

mixture was added to an aqueous solution of NaHCO3 and the organic phases were extracted with EtOAc. The solution

The combined organic was washed with a brine solution, dried (Na2SO4) and concentrated in vacuo. The residue was purified by preparative TLC (5% MeOH in CH2Cl2) to provide H2 (16.5 mg, 59%).

MS: M + H = 437

Example 14, Stage J ', Procedure C

A solution of compound D2 (2.26 g, 4.68 mmol) in CH2Cl2 (20 ml) was treated with acetic anhydride (0.58 ml, 6.08

25 mmol) and triethylamine (1.3 ml, 9.36 mmol) at 0 ° C. The reaction mixture was stirred at 25 ° C for 4 hours. The reaction mixture was added to an aqueous solution of NaHCO3 and the organic solution was extracted with CH2Cl2. The combined organic solution was washed with a brine solution, dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (3% to 10% MeOH in CH2Cl2), yielding intermediate D3 (1.9 g, 78%). A solution of intermediate D3 (518 mg, 0.99 mmol) in CH2Cl2 (18 ml) was treated with chloride

30 p-toluenesulfonyl (207 mg, 1.09 mmol) and triethylamine (0.83 ml, 5.94 mmol) at 25 ° C. The reaction mixture was stirred at 25 ° C for 48 hours. The reaction mixture was added to an aqueous solution of NaHCO3 and the organic solution was extracted with CH2Cl2. The combined organic solution was washed with a brine solution, dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (2.5% 7 N NH3 -MeOH in CH2Cl2) to afford compound J2 (415 mg, 83%). MS: M + H = 507

Example 15, Stage G ', Procedure C

A solution of compound J2 (462 mg, 0.91 mmol) in CH2Cl2 (10 ml) was treated with trifluoroacetic acid (1 ml) at 25 ° C. The reaction mixture was stirred at that temperature for 3 hours. The reaction mixture was concentrated in vacuo and the residual material was dissolved again in CH2Cl2 (6 ml). The solution was treated with 7 N NH3 in MeOH (~ 1 ml) and the

The mixture was stirred for 0.5 hours at 0 ° C. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (3% to 10% MeOH in CH2Cl2) to provide G2 (325 mg, 88%). MS: M + H = 407

Example 16, Stage H "', Procedure C

A solution of compound G2 (429 mg, 1.05 mmol) in CH2Cl2 (18 ml) and THF (4.5 ml) was treated with triethylamine (0.29 ml, 2.1 mmol) and 4-chlorobenzoyl chloride (0.16 ml, 1.26 mmol) at 0 ° C. The reaction mixture was stirred at that temperature for 1.5 hours. The reaction mixture was added to an aqueous solution of NaHCO3 and the organic solution was extracted with CH2Cl2. The combined organic solution was washed with a brine solution, dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel (1.5% to 5% MeOH in

CH2Cl2), providing compound H3 (565 mg, 99%). MS: M + H = 545

Example 17, Stage B ', Procedure C

A cold solution of H3 (hydrochloride salt, 23 mg, 0.039 mmol) in THF (0.5 ml) and water (0.1 ml) was treated with a solution

50% aqueous HBF4 (8 μl) and t-butyl nitrite (8 μl). The reaction mixture was stirred for 16 hours at 25 ° C. The reaction mixture was added to a mixture of CH2Cl2 and an aqueous solution of NaHCO3-NaO (5%). The mixture was stirred for 0.5 hours and the organic phases were extracted with CH2Cl2. The combined organic solution was washed with a brine solution, dried (Na2SO4) and concentrated in vacuo. The residue was purified by preparative TLC (5% MeOH in CH2Cl2), providing B2 (4.3 mg, 19%).

30 MS: M + H = 546

Lithium 2-Amino-6-Chloronicotinate

A solution of 2,6-dichloronicotinic acid (20.2 g, 0.105 mol) in MeOH (500 ml) was cooled to 0 ° C and pure thionyl chloride (38 ml, 63 g, 0.525 mol) was added over 0, 5 hours. The reaction mixture was stirred at 0 ° C for 1 hour. The cooling bath was removed, the reaction temperature was allowed to warm to 25 ° C, and the reaction was allowed to stir for a further 2 days at 25 ° C. The solvent was removed under reduced pressure to give an off-white residue. The residue was dissolved in Et2O (~ 500 ml) and the resulting solution was washed successively with a saturated aqueous solution of NaHCO3 (~ 300 ml), water (~ 300 ml) and brine solution (~ 300 ml). The organic phase was separated, dried over anhydrous MgSO4 and filtered. Removal of the solvent under reduced pressure yielded methyl 2,6-dichloronicotinate (21.0 g, 97%) as a white solid.

Performed in duplicate on identical scales in two pressure vessels, methyl 2,6-dichloronicotinate (4.5 g, 22 mmol) was dissolved in a solution of NH3 (250 ml, 0.5 M in 1,4-dioxane; 0.125 mol). The pressure vessels were sealed and heated at (85 ± 5) ° C for 9 days. The two reaction mixtures were allowed to cool to 25 ° C, then combined and concentrated under reduced pressure to produce a white solid. Dissolution of the solid in 1: 1 acetone-MeOH (~ 500 ml), followed by adsorption on silica gel (25 g) and then purification by flash column chromatography (25: 10: 1 hexane-CH2Cl2-Et2O) , produced 6.08 g (75%) of methyl 2-amino-6-chloronicotinate.

A solution of LiOH H2O (1.38 g, 33 mmol) in water (33 ml) was added in one portion to a suspension of methyl 2-amino-6-chloronicotinate (6.08 g, 27 mmol) in MeOH ( 110 ml) The reaction mixture was stirred at 70 ° C for 24 hours and gradually became homogeneous. The solvents were removed under reduced pressure, and after drying the resulting white solid under vacuum (<1 mmHg) at constant weight, 5.51 g (95%) of lithium 2-amino-6-chloronicotinate were obtained.

Biological examples

The compounds of the invention can be readily evaluated to determine the activity of CXCR3 receptors by known methods, such as, for example, Development of Human CXCR3 Binding Assay (N-delta 4).

Cloning and expression of human CXCR3 (N-delta 4):

DNA encoding human CXCR3 was cloned by PCR using, as template, human genomic DNA (Promega, Madison, WI). PCR primers were designed based on the published sequence of the human orphan receptor GPR9 (1) that incorporated restriction sites, a Kozak consensus sequence, the CD8 leader and a Flag tag. The PCR product was subcloned into the mammalian expression vector pME18Sneo, a derivative of the SR-alpha expression vector (called pME18Sneo-hCXCR3 (N-delta 4))

IL-3 Ba / F3-dependent mouse pro-B cells were transfected by electroporation in PBS with Dulbecco 0.4 ml containing 4 x 106 cells with 20 μg of plasmid DNA pME18Sneo-hCXCR3 (N-delta 4). Cells were driven at 400 Volts, 100 OHMs, 960 μFd. Transfected cells were screened with 1 mg / ml of G418 (Life Technologies Gaithersburg, MD). Ba / F3 clones resistant to G418 were screened for CXCR3 expression by specific binding of [125I] IP-10 (NEN Life Science Products, Boston, MA).

Preparation of membranes Ba / F3-hCXCR3 (N-delta 4)

Ba / F3 cells expressing human CXCR3 (N-delta 4) were sedimented and resuspended in the lysis buffer containing 10 mM HEPES, pH 7.5 and Complete® protease inhibitors (1 tablet per 100 ml) (Boehringer Mannheim, Indianapolis, IN) at a cell density of 20 x 106 cells per ml. After 5 minutes of incubation on ice, the cells were transfected into a 4639 cell disintegration pump (Parr Instrument, Moline, IL) and 1,500 psi of nitrogen was applied for 30 minutes on ice. Large cell debris was removed by centrifugation at 1000 x g. The cell membrane in the supernatant was sedimented at 100,000 x g. The membrane was resuspended in the lysis buffer supplemented with 10% sucrose and stored at -80 ° C. The total membrane protein concentration was determined by the Pierce BCA procedure (Rockford, IL).

Proximity scintillation test (SPA) of human CXCR3 (N-delta 4):

For each test point, 2 μg of membrane was pre-incubated for 1 h with 300 μg of wheat germ agglutinin (AGT) coated with SPA beads (Amersham, Arlington Heights, IL) in the binding buffer (50 mM HEPES, CaCl2 1 mM, 5 mM MgCl2, 125 mM NaCl, 0.002% NaN3, 1.0% BSA) at room temperature. The beads were centrifuged, washed once, resuspended in the binding buffer and transferred to a 96-well Isoplaca (Wallac, Gaithersburg, MD). To initiate the reaction, 25 pM of [125I] IP-10 was added with the test compounds in a titration series. After 3 h of reaction at room temperature, the amount of bound [125I] IP-10 was determined

5 to SPA pearls with a Wallac 1450 Microbeta counter.

Ki values for the various compounds of the examples of the present invention are provided in Table 1 mentioned above. From these values, it would be apparent, to those skilled in the art, that the compounds of the present invention had excellent utility as CXCR3 antagonists.

Although the present invention has been described in conjunction with the specific embodiments set forth above, many

10 alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All these alternatives, modifications and variations are intended to be included within the spirit and scope of the present invention.

Claims (32)

1. A compound that has the general structure shown in Formula 1: or a pharmaceutically acceptable salt, solvate or ester thereof, in which: G is selected from the group consisting of H, hydroxyl, alkoxy, R2R1N-, R2R1X-C (R14) (R1S) - and a 5-membered heteroaryl or heterocyclynyl ring containing at least one -C = N- moiety as part of said heteroaryl or heterocyclynyl ring and which is selected from the group consisting of dihydroimidazole, imidazole, dihydrooxazol, oxazol, dihydrooxadiazole, oxadiazole, triazole and tetrazole, wherein said heteroaryl or heterocyclynyl ring may be both (i) unsubstituted, and (ii) optionally independently substituted in one or more carbon atoms in the ring with one or more R9 substituents, or in one or more ring nitrogen atoms with one or more R8 substituents, wherein said R8 and R9 substituents may be same or different; L is O Z is No CR4; R1 and R2 are absent or present independently, and if present, each is independently selected from the group consisting of H, alkyl, alkoxy, alkenyl, carbonyl, cycloalkyl, cycloalkenyl, alkylaryl, arylalkyl, aryl, amino, alkylamino, amidinyl , carboxamido, cyano, hydroxyl, urea, -N≡CH, = NCN, - (CH2) qOH, - (CH2) qOR31, - (CH2) qNH2, - (CH2) qNHR31, (CH2) qN (R31) 2, - (CH2) qC (= O) NHR31, - (CH2) qSO2R31, - (CH2) qNHSO2R31, - (CH2) qSO2NHR31, -C (= S) N (H) alkyl, -N (H) -S (O ) 2-alkyl, -N (H) C (= O) N (H) -alkyl, -S (O) 2alkyl, -S (O) 2N (H) alkyl, - S (O) 2N (alkyl) 2 , -S (O) 2-aryl, -C (= S) N (H) cycloalkyl, -C (= O) N (H) NH2, -C (= O) alkyl, -heteroaryl, heterocyclyl and heterocyclyl; or alternatively, when X is N, the N taken together with R1 and R2 forms a heterocyclyl, heteroaryl or -N = C (NH2) 2; R3 is selected from -H, -Cl and -CH3 the R4 moieties may be the same or different, each independently being selected from the group consisting of H, alkyl, alkylaryl, aralkyl, -CN, CF3, haloalkyl, cycloalkyl, halogen, hydroxyalkyl, -N = CH- (R31), -C (= O) N (R31) 2, -N (R30) 2, -OR30, -SO2 (R31), -N (R30) C (= O) N (R30) 2 and -N (R30) C (= O) R31; R6 is selected from the group consisting of H and alkyl, X is selected from the group consisting of N, O, alkyl, cycloalkyl, heteroaryl, heterocyclyl and heterocyclyl; R8 moieties may be the same or different, each independently being selected from the group consisting of H, alkyl, alkenyl, alkylaryl, arylalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, - (CH2) qOH, - (CH2) qOR31, - (CH2) qNH2, - (CH2) qNHR31, - (CH2) qC (= O) NHR31, - (CH2) qSO2R31, - (CH2) qNSO2R31 and - (CH2) qSO) 2NHR31; residues R9 may be the same or different, each independently being selected from the group consisting of -NH2 and -N (H) CH2CH3 residues R10 may be the same or different, each independently selected from the group consisting of CH3, CH2CH3 and -CH2 CH2 CH3 the R11 moieties may be the same or different, each independently selected from the group consisting of H and CH3 the R12 moieties are -H the D ring is selected from phenyl and pyridinyl, in which the D ring is unsubstituted or optionally substituted with 1-5 independently selected R20 moieties; R20 moieties may be the same or different, each independently selected from the group consisting of -H, halogen and amino. R21 moieties may be the same or different, each independently being selected from the group consisting of H, alkyl, alkenyl, alkylaryl, alkynyl, alkoxy, alkylamino, alkylthiocarboxy, alkylheteroaryl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, aminoalkyl, amidinyl, aralkyl , aralkenyl, aralkoxy, aralkoxycarbonyl, aralkylthio, aryl, aroyl, aryloxy, carboxamido, cyano, cycloalkyl, cycloalkenyl, formyl, guanidinyl, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, heterocyclenyl, hydroxyalkyl, hydroxamate, nitro, trifluoromethoxy, - (CH2 ) qOH, - (CH2) qOR31, - (CH2) q-NH2, - (CH2) qNHR31, - (CH2) qC (= O) NHR31, - (CH2) qSO2R31, - (CH2) qNSO2R31, - (CH2) qS2NHR31, -alquinylC (R31) 2OR31, -C (= O) R30, -C (= O) N (R30) 2, -C (= NR30) NHR30, -C (= NOH) N (R30) 2, -C (= NOR31) N (R30) 2, -C (= O) OR30, -N (R30) 2; -N (R30) C (= O) R31, -NHC (= O) N (R30) 2, -N (R30) C (= O) OR31, -N (R30) C (= NCN) N (R30) 2, -N (R30) C (= O) N (R30) SO2 (R30), -N (R30) C (= O) N (R30) 2, -N (R30) SO2 (R31), -N (R30) S (O) 2N (R30) 2, -OR30, -OC (= O) N (R30) 2, -SR30, -SO2N (R30) 2, -SO2 (R31), -OSO2 (R31) and -OSi (R30) 3; And it is selected from the group consisting of -CH2 - and -C (= O) - R13 residues may be the same or different, each independently selected from the group that It consists of H, alkyl, alkylaryl, cycloalkyl, alkoxy, aryl, heteroaryl, heterocyclynyl, heterocyclyl, spiroalkyl, -CN, -CO2H, -C (= O) R30, -C (= O) N (R30) 2, - (CHR30) qOH, - (CHR30) qOR31, - (CHR30) qNH2, - (CHR30) qNHR31, - (CH2) qC (= O) NHR31, - (CH2) q-SO2R31, - (CH2) qNSO2R31, - (CH2) qSO2NHR31, -NH2, -N (R30) 2, -N (R30) C (= O ) N (R30) 2, -N (R30) SO2 (R31), -OH, OR30, -SO2N (R30) 2 and -SO2 (R31); R14 and R15 are the same or different, each independently selected from the group consisting of H, alkyl, alkylaryl, heteroaryl, hydroxy, -CN, alkoxy, alkylamino, -N (H) S (O) 2alkyl and -N (H) C (= O) N (H) alkyl; or alternatively R14 and R15 taken together are = O, = S, = NH, = N (alkyl), = N (Oalkyl), = N (OH) or cycloalkyl; R30 residues may be the same or different, each independently selected from the group that consists of H, alkyl, alkylaryl, aryl, aralkyl, cycloalkyl, - (CH2) qOH, - (CH2) qOalkyl, - (CH2) qOalkylaryl, - (CH2) qOaryl, - (CH2) qOaralkyl, - (CH2) qOcycloalkyl, - (CH2) qNH2, - (CH2) qNHalkyl, - (CH2) qN (alkyl) 2, - (CH2) qNHalkylaryl, - (CH2) qNHaryl, - (CH2) qN-Haralkyl, - (CH2) qNHcycloalkyl, - (CH2) qC (= O) NHalkyl, - (CH2) qC (= O) N (alkyl) 2, - (CH2) qC (= O) NHalkylaryl, - (CH2) qC (= O) NHaryl, - (CH2) qC (= O) NHaralkyl, - (CH2) qC (= O) NHcycloalkyl, - (CH2) qSO2alkyl, - (CH2) qSO2alkylaryl, - (CH2) q-SO2aryl, - (CH2) qSO2aralkyl, - (CH2) qSO2cycloalkyl, - (CH2) qNSO2alkyl, - (CH2) q-NSO2alkylaryl, - (CH2) qNSO2aryl, - (CH2) qNSO2aralkyl, - (CH2) qNSO2cycloalkyl, - (CH2) qSO2NHalkyl, - (CH2) qSO2NHalkylaryl, - (CH2) qSO2NHaryl, - (CH2) qSO2NHaralkyl, - (CH2) qSO2NHcycloalkyl, heterocyclyl, heterocyclyl and heteroaryl; R31 residues may be the same or different, each independently selected from the group that consists of alkyl, alkylaryl, aryl, aralkyl, cycloalkyl, - (CH2) qOH, - (CH2) qOalkyl, - (CH2) qOalkylaryl, - (CH2) qOaryl, - (CH2) qOaralkyl, - (CH2) qOcycloalkyl, - (CH2) qNH2, - (CH2) qNHalkyl, - (CH2) qN (alkyl) 2, - (CH2) qNHalkylaryl, - (CH2) qNHaryl, - (CH2) qNHaralkyl, - (CH2) qNHcycloalkyl, - (CH2) qC (= O) NHalkyl, - (CH2) qC (= O) N (alkyl) 2, - (CH2) qC (= O) NHalkylaryl, - (CH2) qC (= O) NHaryl, - (CH2) qC (= O) NHaralkyl, - (CH2) qC (= O) NHcycloalkyl, - (CH2) qSO2alkyl, - (CH2) qSO2-alkylaryl, - (CH2) q-SO2aryl, - (CH2) qSO2aralkyl, - (CH2) qSO2cycloalkyl, - (CH2) qNSO2alkyl, - (CH2) qNSO2alkylaryl, - (CH2) qNSO2aryl, - (CH2) qNSO2aralkyl, - (CH2) qNSO2cycloalkyl, - (CH2) qSO2NHalkyl, - (CH2) qSO2NHalkylaryl, - (CH2) qSO2NHaryl, - (CH2) qSO2NHaralkyl, - (CH2) qSO2NHcycloalkyl, heterocyclyl, heterocyclyl and heteroaryl; m is 0 to 2; n is from 0 to 4; Y each q may be the same or different, each time being independently selected from 1 to 5; where the following definitions apply: "heteroaryl" means an aromatic, monocyclic or multicyclic ring system, comprising about 5 to about 14 atoms in the ring, in which one or more of the atoms in the ring are a different element of carbon; the "heteroaryl" may be optionally substituted; "heterocyclynyl" means a partially unsaturated monocyclic or partially multicyclic ring system unsaturated comprising from about 5 to about 14 atoms in the ring, in which one or more of the atoms in the ring are a different element of carbon; the "heterocyclenyl" may optionally be replaced; "heterocyclyl" (or heterocycloalkyl) means a saturated non-aromatic monocyclic ring system or multicyclic comprising from about 3 to about 10 atoms in the ring, in which one or more of the Atoms in the ring system are a distinct element of carbon; the heterocyclyl can be optionally replaced; with the proviso that there are not two adjacent double bonds in any ring, and that when a nitrogen is substituted with two alkyl groups, said two alkyl groups can optionally be linked together to form a ring.

2.

 The compound according to Claim 1, wherein G is R2R1X-C (R14) (R1S) -.

3.

 The compound according to Claim 2, wherein X is N, and R14 and R15 taken together are = O.

Four.

 The compound according to Claim 3, wherein R1 and R2 are both H.

5.

 The compound according to Claim 1, wherein G is selected from the group consisting of H, hydroxyl; alkyl- or R2R1N.

6.

 The compound according to claim 1, wherein G is

7.

 The compound according to Claim 1, wherein R8 is selected from the group consisting of H, alkyl, alkenyl, arylalkyl, cycloalkyl, - (CH2) qOH, - (CH2) qOR31, - (CH2) qNH2, - (CH2) qNHR31, - (CH2) qC (= O) NHR31, - (CH2) qSO2R31, - (CH2) qNSO2R31 and - (CH2) qSO2NHR31.

8.

 The compound according to claim 1, wherein R10 is -CH2CH3 and m is 1.

The compound according to Claim 1, wherein R11 is H.

10.

The compound according to claim 1, m is 1.

eleven.

 The compound according to Claim 1, wherein n is 0-2.

12.

 The compound according to claim 1, wherein n is 0.

13.

 The compound according to claim 1, wherein q is 1 or 2.

14. The compound according to Claim 1, wherein G is independently selected from the group consisting of R2R1N-C (= O) - and R10 is -CH2CH3; R11 is H; 20 m is 1; and n is 0. 15. A compound according to Claim 1, wherein the compound is selected from the group consisting of the following: or a pharmaceutically acceptable salt, solvate or ester thereof. 16. A compound according to Claim 15, wherein the compound is selected from the group consisting of or a pharmaceutically acceptable salt, solvate or ester thereof.

17.

 A compound, according to claim 1, in purified form.

18.

 A pharmaceutical composition comprising at least one compound of claim 1, or a salt, a solvate

5 or a pharmaceutically acceptable ester thereof, in combination with at least one pharmaceutically acceptable carrier. 19. The pharmaceutical composition of claim 18, further comprising at least one additional agent, drug, medicament, antibody and / or inhibitor for the treatment of a disease mediated by the chemokine receptor CXCR3. A compound according to any one of claims 1-17, for use in a method for the treatment of a disease mediated by the CXCR3 chemokine receptor in a patient in need of such treatment, which comprises administering to the patient an amount Therapeutically effective of at least one compound of this type or a pharmaceutically acceptable salt, solvate or ester thereof. 21. A compound for use in a method according to claim 20, wherein the method comprises administering to the patient (a) an effective amount of at least one such compound or a salt, a solvate or a pharmaceutically acceptable ester thereof, simultaneously or sequentially with (b) at least one additional agent, drug, medication, antibody and / or inhibitor for the treatment of a disease mediated by the chemokine receptor CXCR3, in combination with a pharmaceutically acceptable vehicle. 22. The compound for use in a process according to claim 20, in the compound binds to the CXCR3 receptor. 23. The compound for use in a process according to claim 20, wherein the process comprises administering: (a) a therapeutically effective amount of at least one such compound, or a salt, a solvate or an ester pharmaceutically acceptable thereof, simultaneously or sequentially with (b) at least one drug selected from the group consisting of: disease modifying antirheumatic drugs; 25 non-steroidal anti-inflammatory drugs; selective COX-2 inhibitors, COX-1 inhibitors; immunosuppressants, steroids, PDE IV inhibitors, anti-TNF-α compounds, TNF-alpha-convertase inhibitors, inhibitors of cytokine, MMP inhibitors, glucocorticoids, chemokine inhibitors, selective CB2 inhibitors, p38 inhibitors, biological response modifiers; therapeutic agents and anti-inflammatory compounds.

24.

 The compound for use in a method according to claim 20, wherein the disease is an inflammatory disease.

25.

 A compound according to any of claims 1-17, for use in a method for inhibiting or blocking T-cell mediated chemotaxis in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of at least a compound of this type or a pharmaceutically acceptable salt, solvate or ester thereof.

26.

 A compound according to any of claims 1-17, for use in a procedure for the treatment of inflammatory bowel disease in a patient in need of such treatment, which comprises administering to the patient a therapeutically effective amount of at least one compound of this pharmaceutically acceptable type or salt, solvate or ester thereof.

27.

 A compound according to any of claims 1-17, for use in a procedure for the treatment or prevention of graft rejection in a patient in need of such treatment, which comprises administering to the patient a therapeutically effective amount of at least one compound of this type or a pharmaceutically acceptable salt, solvate or ester thereof.

28.

 The compound for use in a method according to claim 27, wherein the method comprises administering to the patient a therapeutically effective amount of: (a) at least one such compound or a salt, a solvate or an ester of the same pharmaceutically acceptable, simultaneously or sequentially with (b) at least one compound selected from the group consisting of: cyclosporine, A, FK-506, FTY720, beta-interferon, rapamycin, mycophenolate, prednisolone, azathioprene, cyclophosphamide and a globulin antilymphocytic

29.

 A compound according to any of claims 1-17, for use in a method for the treatment of multiple sclerosis in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of: (a) at least a compound of this type or a pharmaceutically acceptable salt, solvate or ester thereof, simultaneously or sequentially with (b) at least one compound selected from the group consisting of: beta-interferon, glatiramer acetate, glucocorticoids, methotrexate , azothioprine, mitoxantrone, VLA-4 inhibitors and selective CB2 inhibitors.

30

 A compound according to any of claims 1-17, for use in a method for the treatment of multiple sclerosis in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of: (a) at least a compound of this type or a pharmaceutically acceptable salt, solvate or ester thereof, simultaneously or sequentially with (b) at least one compound selected from the group consisting of: methotrexate, cyclosporine, leflunimide, sulfasalazine, β-metasona , β-interferon, glatiramer acetate, prednisone, etonercept and infliximab.

31.

 A compound according to any of claims 1-17, for use in a procedure for the treatment of rheumatoid arthritis in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of: (a) at least such a compound or salt, a pharmaceutically acceptable solvate or ester thereof, simultaneously or sequentially with (b) at least one compound selected from the group consisting of: COX-2 inhibitors, COX-1 inhibitors, immunosuppressants , steroids, PDE IV inhibitors, anti-TNF-α compounds, MMP inhibitors, glucocorticoids, chemokine inhibitors, selective CB2 inhibitors, caspase inhibitors (ICE) and other classes of compounds indicated for the treatment of rheumatoid arthritis.

32

 A compound according to any of claims 1-17, for use in a procedure for the treatment of psoriasis in a patient in need of such treatment, the method comprising administering to the patient a therapeutically effective amount of: (a) at least one compound of this type or a pharmaceutically acceptable salt, solvate or ester thereof, simultaneously or sequentially with (b) at least one compound selected from the group consisting of: immunosuppressants, steroids and anti-TNF-α compounds.

33.

 A compound according to any of claims 1-17, for use in a method for the treatment of a disease selected from the group consisting of: inflammatory disease, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, graft rejection, psoriasis , drug-fixed rashes, delayed skin hypersensitivity responses, tuberculoid leprosy and cancer in a patient in need of such treatment, such procedure comprising administering to the patient an effective amount of at least one such compound or a salt, a solvate or a pharmaceutically acceptable ester thereof.

3. 4.

 A compound according to any of claims 1-17, for use in a method for the treatment of a disease selected from the group consisting of: inflammatory disease, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, graft rejection, psoriasis , drug-fixed rashes, delayed skin hypersensitivity responses and tuberculoid leprosy, type I diabetes, viral meningitis and cancer in a patient in need of such treatment, such a procedure comprising administering to the patient a

effective amount of (a) at least one compound of this type or a pharmaceutically acceptable salt, solvate or ester thereof, simultaneously or sequentially with (b) at least one drug selected from the group consisting of: anti-rheumatic modifying drugs diseases, non-steroidal anti-inflammatory drugs; selective COX-2 inhibitors; COX-1 inhibitors; immunosuppressants; steroids; PDE IV inhibitors, anti-TNF-α compounds, MMP inhibitors, glucocorticoids, chemokine inhibitors, selective CB2 inhibitors, biological response modifiers; therapeutic agents and anti-inflammatory compounds.

35

 A compound according to any of claims 1-17 for use in therapy.